TW202535397A - Dosing regimen - Google Patents

Abstract

A compound of Formula (I): or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of a disease or condition in which inhibition of JAK1 is beneficial, wherein said treatment comprises the administration of the Compound of Formula (I) or pharmaceutically acceptable salt thereof, in a daily delivered dose of from 0.8 mg to 6.2 mg of the free base to a subject.

Description

Medication regimen

This disclosure relates to methods for treating or preventing diseases and disorders of therapeutic significance by inhibiting JAK1 function.

The JAK (Janus-associated kinase) family includes three receptor-binding tyrosine kinases, JAK1, JAK2, and JAK3, as well as the non-receptor-binding member Tyk2, all of which play key roles in cytokine and growth factor-mediated signal transduction (Schindler C 1995). JAK1, in particular, interacts with receptors of type I interferons (e.g., IFNα), type II interferons (e.g., IFNγ), common γ-chain γc (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), and the interleukin-6 family (IL-10, IL-13, and IL-22) (O'Shea 2013). Upon binding to their receptors, these intercytokines undergo receptor oligomerization, leading to the migration of the cytoplasmic tail of the associated JAK kinase to the vicinity and promoting transphosphorylation and activation of the tyrosine residue on the JAK kinase. Phosphorylated JAK kinase binds to and activates various signal transducers and transcription activators (STAT) proteins. These STAT proteins then dimerize and translocate to the nucleus, where they function as signal transduction molecules and transcription factors, ultimately binding to specific DNA sequences present in the promoters of intercytokine-responsive genes (Leonard 2000). Various immunodeficiency and autoimmune diseases, such as allergies, asthma, alopecia areata, transplant (allogeneic graft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and solid and hematologic cancers, are caused by disruptions in signaling pathways in the JAK/STAT pathway. See, for example, Frank 1999, Vijayakriishnan 2011 and Laurence 2012, O’Shea 2013, Ghoreschi 2014, Clark 2014, Ashino 2014, and Herrera 2015.

A key element of JAK1 is its ability to pair with other JAK kinases at intracellular domains of different subunits of the receptor. For example, JAK3 binds to the common γ-chain (γc) of various intercytokine receptors and pairs with JAK1 (Pesu 2008). JAK1 has been shown to be superior to JAK3, and although JAK3 is active, inhibition of JAK1 is sufficient to inactivate signaling via the common γ-chain (Haan 2011). Therefore, selective inhibition of JAK1 could be sufficient to treat a variety of inflammatory and autoimmune diseases associated with intercytokine signaling via the JAK1/JAK3-STAT pathway.

Examples of JAK1-related conditions include leukemia, lymphoma, transplant rejection (e.g., islet transplant rejection, bone marrow transplantation applications (e.g., graft-versus-host disease)) and autoimmune/inflammatory diseases (e.g., type 1 diabetes, allergic reactions, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis arthritis, juvenile idiopathic arthritis, axial spondylitis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), leukoplakia, and alopecia areata).

Asthma is a heterogeneous disease typically characterized by chronic airway inflammation and bronchial hyperresponsiveness. Asthma is defined by respiratory symptoms (such as wheezing, shortness of breath, chest tightness, and cough) that vary over time and in intensity, as well as a history of variable expiratory airflow obstruction. The JAK1-STAT6 pathway is a particularly attractive target in the context of T2 asthma because key T2 intercytokines IL-4 and IL-13 activate JAK1, which in turn phosphorylates STAT6, leading to T2 inflammatory processes including eosinophil recruitment and activation, antibody class conversion to immunoglobulin E production, goblet cell proliferation and excessive mucus secretion, and airway hyperresponsiveness and remodeling.

WO2018/134213 teaches examples of compounds that selectively inhibit JAK1, including (( R )-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonylurea)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propionamide, the structure of which is shown below, and is referred to as "Compound of Formula I" or "Compound 1". (I).

WO2018/134213, US2019/367490A1, and US2021/188821A1 (the contents of which are hereby incorporated herein by reference in their entirety) describe additional JAK inhibitory compounds, including various salts of ( R )-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonylmethane)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propionamide. The synthesis of compound 1 is described in WO2018/134213 (Example 35) and Pithani 2023.

WO2020/016302 and US2020/062737A1 (the contents of which are hereby incorporated in their entirety) disclose a xinafoate salt of compound 1 and a method for preparing the salt.

JAK inhibitors have immunosuppressive properties. Potential risks associated with administration of compound 1 are based on non-clinical studies and approved drugs with similar mechanisms of action (i.e., oral JAK inhibitors). In non-clinical studies, high doses of compound 1 reduced lymphocyte and eosinophil counts in rats, but only with systemic exposure greater than expected human exposure. Orally administered JAK inhibitors (primarily used for rheumatoid arthritis) are associated with various infections such as pneumonia, herpes zoster, urinary tract infections, and skin or soft tissue infections. The risks of pneumonia and herpes zoster are recognized as common adverse reactions to most oral JAK inhibitors (tofacitinib). JAK inhibitors, due to their anti-inflammatory properties, pose a potential risk of adversely affecting antiviral responses. Additionally, patients with low absolute lymphocyte counts have an increased risk of serious infections (Van Vollenhoven 2019). Furthermore, in 2021, the FDA issued a black box warning for three oral JAK inhibitors—tofacitinib, baricitinib, and upadacitinib—regarding an increased risk of serious cardiac events (such as heart attack, stroke, cancer, thrombosis, and death).

Compound 1 is being developed for the treatment of asthma via inhalation to maximize local efficacy in the lungs. The systemic exposure of compound 1 is lower than that of oral JAK inhibitors, resulting in a significantly improved safety profile compared to oral JAK inhibitors. To deliver compound 1 to patients, a dosing regimen needs to be developed to provide effective treatment with an improved safety profile compared to currently approved JAK1 inhibitors.

In some embodiments, a method for treating or preventing JAK1 inhibition that is beneficial is disclosed, comprising administering compound (I) (also referred to as compound 1) to an individual in need at a daily dose of 0.8 mg to 6.2 mg of free base: (I) or a medically acceptable salt thereof.

In some embodiments, a method for treating or preventing JAK1 inhibition that is beneficial to a disease or ailment is disclosed, comprising administering compound 1 to an individual twice daily in a delivery dose of 0.4 mg to 3.1 mg of free base, wherein compound 1 may be in the form of a pharmaceutically acceptable salt.

In some embodiments, it is disclosed that compound 1 or a pharmaceutically acceptable salt thereof is beneficial for the treatment or prevention of JAK1 inhibition of a disease or ailment, wherein the treatment comprises administering compound 1 to the individual at a daily dose of 0.8 mg to 6.2 mg of free base.

In some embodiments, it is disclosed that compound 1 or a pharmaceutically acceptable salt thereof is beneficial for the treatment or prevention of JAK1 inhibition of a disease or ailment, wherein the treatment comprises administering compound 1 to the individual in a delivery dose of 0.4 mg to 3.1 mg of free base twice daily.

In some embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease or ailment in which JAK1 inhibition is beneficial, wherein the treatment comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient at a daily dose of 0.8 mg to 6.2 mg of free base.

In some embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a delivery dose of 0.4 to 3.1 mg of free base twice daily.

In at least one embodiment, this disclosure includes the preparation of compound 1 as a sine (1-hydroxy-2-naphthoic acid) salt (formula (Ia)): Formula (Ia)

4-{( 2R )-1-[(3-{5-fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl} -1H -indol-7-yl)amino]-3-methoxy-1-epoxypropane-2-yl}-1-methylpiperazin-1-onyl;1-hydroxynaphthalene-2-carboxylate.

In some embodiments, compound 1 is administered in daily doses of 0.8 mg, 1.8 mg, 2.8 mg or 6.0 mg of free base.

In some embodiments, compound 1 is administered as a delivery dose of 1.4 mg twice daily, 0.9 mg twice daily, 0.4 mg twice daily, or 3.0 mg twice daily of free base.

In some embodiments, the compound of formula (I) is administered as a sine benzoate at a daily delivery dose of 1.05 mg to 8.14 mg sine benzoate.

In some embodiments, the sine benzoate of the compound of formula (I) is administered in a delivery dose of 1.84 mg, 1.18 mg, 0.53 mg or 3.94 mg sine benzoate twice daily.

In some embodiments, JAK1 inhibition is beneficial for diseases or disorders selected from type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis arthritis, juvenile idiopathic arthritis, axial spondylitis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata.

In some embodiments, JAK1 inhibition is a beneficial disease or condition such as COPD or asthma.

In some embodiments, a kit is disclosed for a method of treating or preventing diseases or disorders in which JAK1 inhibition is beneficial, the kit comprising an inhaler that delivers a compound of formula (I) in a daily dose of 0.8 mg to 6.2 mg of free base, wherein the compound of formula (I) may be in the form of a pharmaceutically acceptable salt. In some embodiments, the inhaler is a dry powder inhaler or a metered-dose inhaler.

In some embodiments, an inhaler is disclosed that is formulated to deliver a compound of formula (I) at a dose of 0.4 mg to 3.1 mg of free base, wherein the compound of formula (I) may be in the form of a pharmaceutically acceptable salt. In some embodiments, the inhaler is a dry powder inhaler or a metered-dose inhaler.

In the Phase 1 study described in more detail below, it was surprising that no major safety or tolerability issues were identified up to the maximum prescribed dose. No serious adverse events or deaths were reported in this part of the study. Overall, the researchers considered all reported adverse events to be mild or moderate in intensity, except for one adverse event which was considered to be severe.

In participants with mild asthma receiving twice-daily doses of 1.4 mg and 3.0 mg, a 50% reduction in exhaled nitric oxide fraction (FeNO), a biomarker of lung inflammation, was observed compared to placebo. FeNO data also demonstrated a good effect before and after administration, proving that the twice-daily regimen provides 24-hour coverage.

The 1.4 mg twice-daily (BID) dose was found to be safe and well-tolerated, and resulted in a reduction of approximately 50% in the inflammatory biomarker of FeNO in the lungs of participants with mild asthma compared to placebo. This level of FeNO reduction is considered a good indicator of potential clinical efficacy.

This disclosure includes combinations of the described patterns and certain features, unless such combinations are clearly not permitted or explicitly avoided.

Cross-reference to related applications This application claims priority and interests in UK Patent Application No. 2316063.3, filed on October 20, 2023. The entire contents of this application are hereby incorporated herein by reference.

The forms and embodiments will now be discussed with reference to the accompanying figures. Other forms and embodiments will be readily apparent to those skilled in the art. All documents mentioned herein are incorporated herein by reference. Salt

In some embodiments, a free alkali compound 1 is administered to an individual. In some embodiments, a pharmaceutically acceptable salt of compound 1 is administered to an individual. In some embodiments, crystalline compound 1 or a pharmaceutically acceptable salt of compound 1 is administered to an individual.

The term "pharmaceutically acceptable salts" includes acid addition salts that retain the bioavailability and properties of compound 1. Pharmaceutically acceptable salts can be formed using inorganic or organic acids, such as acetates, aspartate salts, benzoates, benzenesulfonates, bromides/hydrobromoates, bicarbonates/carbonates, bisulfates/sulfates, camphorsulfonates, chlorides/hydrochlorides, theophylline, citrates, ethanedisulfonates, fumarates, glucoheponicates, gluconates, glucuronates, hippurates, hydroiodates/iodides, hydroxyethanesulfonates, lactates, and lactose. Salts, lauryl sulfate, malic acid salts, cis-butenedioic acid salts, malonate salts, mandelic acid salts, methanesulfonate salts, methyl sulfate salts, naphtholate salts, naphthalenesulfonate salts, niacinate salts, nitrate salts, octadecanoate salts, oleate salts, oxalate salts, palmitate salts, palmoate salts, palmoate salts, phosphates/hydrogen phosphates/dihydrogen phosphates, polygalacturonic acid salts, propionates, stearates, succinates, salicylates, tartrates, toluenesulfonates, and trifluoroacetates. Inorganic acids that can be derived into salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and similar acids. Organic acids that can be derived into salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, and similar acids.

In some embodiments, compound 1 is administered as a sine salt (1-hydroxy-2-naphthoic acid) (formula (Ia)): Formula (Ia).

4-{( 2R )-1-[(3-{5-fluoro-2-[2-fluoro-3-(methanesulfonyl)anilino]pyrimidin-4-yl} -1H -indol-7-yl)amino]-3-methoxy-1-ephthylpropane-2-yl}-1-methylpiperazin-1-on;1-hydroxynaphthalene-2-carboxylate. Pharmaceutical composition .

In at least one embodiment, this disclosure includes a pharmaceutical composition comprising compound 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

The phrase "pharmaceutically acceptable excipients, carriers, or diluents" includes compounds, materials, compositions, and/or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and whose benefits/risks are proportionate. Pharmaceutically acceptable excipients, carriers, and diluents are well known in the art, and any choice of pharmaceutically acceptable excipients, carriers, and diluents in practice depends on the intended use and method of administration of the pharmaceutical composition.

The formulation, administered by inhalation and/or blowing, may be in the form of a conventional pressurized aerosol, which is arranged to dispense the active ingredient as an aerosol containing fine solid or droplet fragments. Conventional aerosol propellants such as volatile fluorides may be used, and the aerosol device is conveniently arranged to dispense metered amounts of the active ingredient. For further information on formulations, please refer to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press, 1990, Vol. 5, Chapter 25.2.

A nebulizer is a drug delivery device used to administer medication in the form of a mist inhaled into the lungs. Different types of nebulizers are known to those skilled in the art and include jet nebulizers, ultrasonic nebulizers, and vibrating screen technology. Some nebulizers provide a continuous stream of nebulized solution, meaning they provide continuous nebulization over a long period of time, regardless of whether the individual inhales it, while other nebulizers are respiration-driven, meaning the individual only receives a dose when inhaled through the nebulizer.

A non-pressurized metered-dose inhaler (MDI), also known as a soft-mist inhaler, is a device that delivers a specific amount of medication to the lungs in a short burst of liquid aerosol. This type of metered-dose inhaler typically consists of three main components: a canister containing the medication to be dispensed; a metering valve that allows dispensing a metered amount of medication with each actuation; and an actuator (or mouthpiece) that allows the patient to operate the device and direct the liquid aerosol to the patient's lungs.

Dry powder inhalers (DPIs) deliver medication to the lungs in the form of dry powder. DPIs are typically used to treat diseases or conditions that are beneficial to the lungs when applied topically, such as respiratory illnesses like asthma and COPD. However, DPIs can also be used to administer medications for other conditions. Examples of DPI devices include TURBUHALER, GENUAIR, and DISKUS.

In some embodiments, compound 1 is administered as an inhaled aerosol. In some embodiments, compound 1 is administered as a dry powder. In some embodiments, compound 1 is administered using a metered-dose inhaler. In some embodiments, compound 1 is administered using a dry powder inhaler.

The amount of active ingredient in combination with one or more excipients to produce a single dosage form will necessarily vary depending on the host being treated and the specific route of administration. For further information on routes of administration and dosage regimens, please refer to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press, 1990, Vol. 5, Chapter 25.3. Depending on the potency and physical characteristics of, for example, compound 1 and its pharmaceutically acceptable salt (i.e., the active ingredient), pharmaceutical compositions that may be mentioned include those containing an active ingredient at least 1% (or at least 10%, at least 30%, or at least 50%) by weight. Dosage

In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered orally. In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered by inhalation and/or blowing. In some embodiments, compound 1 is in the form of a conventional pressurized aerosol arranged to dispense the active ingredient into an aerosol containing fine solid or droplets.

Compound 1 can be delivered to the lungs as a free alkali (i.e., the active pharmaceutical ingredient) or as a pharmaceutically acceptable salt. The amounts of free alkali and salt will differ slightly, but the same amount of active ingredient will be delivered via aerosol.

The dosage mentioned refers to the amount of active ingredient dispensed by a self-taught pressurized aerosol. The amount of active ingredient reaching the lungs can vary due to many different factors such as mechanical barriers (including the impaction of inhaled drug particles in the mouth and nose, and the loss of delivery to the peripheral lung areas due to impaction in the large airways), the effects of disease (such as airway narrowing, excessive mucus secretion, and mucus blockage), and the removal of the drug by the pulmonary mucosal cilia clearance.

As used herein, "local exposure" refers to the presence of a sufficient level of inhaled compound 1 in the lungs to interact with its target. This can occur without detectable target binding in the blood or measurable concentrations of compound 1 in the blood or serum. The level of lung target binding can increase with increasing inhaled dose levels, and this can also be correlated with substantial inhibition of target binding in the blood and measurable concentrations of compound 1 in the blood or serum. The term "local lung exposure" refers to the lung concentration of inhaled compound 1, which is responsible for its lung target binding. A decrease in the fractional nitric oxide (FeNO) in exhaled breath can be used to determine whether sufficient "local exposure" has been achieved. In some other cases, especially in the case of humans, since it is difficult to directly measure the amount of compound 1 remaining in the lungs, "local exposure" or "local lung exposure" can be indirectly determined by measuring the amount of compound 1 entering the circulatory system.

In some embodiments, compound 1 is administered to an individual at least once daily. In some embodiments, compound 1 may be administered to an individual once daily. In some embodiments, compound 1 may be administered to an individual twice daily.

In some embodiments, compound 1 is administered to an individual continuously. In some embodiments, compound 1 is administered to an individual twice daily. In some embodiments, compound 1 is used as a long-term maintenance drug.

In some embodiments, compound 1 is administered twice daily at any time of day. In some embodiments, compound 1 is administered at any time of day or night when the individual feels the need to respond to symptoms. In some embodiments, compound 1 is administered once in the evening and once in the morning. In some embodiments, compound 1 is administered by inhalation once in the morning and once in the evening. In some embodiments, compound 1 is administered by inhalation twice, once in the morning and once in the evening.

In some embodiments, the doses are administered 10 to 14 hours apart. In other embodiments, the doses are administered 11 hours and 30 minutes to 12 hours and 30 minutes apart.

In the methods of treating asthma disclosed herein, the delivery dose of compound 1 is approximately 0.8 to approximately 6.2 mg of free base per day. The amount of free base is the amount of the active pharmaceutical ingredient, i.e., the amount of the active ingredient (API). "Delivery dose" refers to the amount of compound 1 delivered to an individual, i.e., the amount exhaled or administered via an inhalation device during administration.

In some embodiments, compound 1 is administered at a daily dose of about 0.8 mg to about 6.2 mg of free base. In some embodiments, compound 1 is administered in the form of a pharmaceutically acceptable salt at a daily dose of 0.8 mg to 6.2 mg of free base. Therefore, in some embodiments, the daily dosage may be 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, or 5.3 mg per day. 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg, or 6.2 mg. These dosages refer to the delivery dose of free base.

In some implementations, the daily delivery dose may be at least 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, or 5.3 mg per day. mg, 5.4 mg or 5.5 mg of free alkali.

In some embodiments, compound 1 is administered at doses of up to 6.2 mg, 6.1 mg, 6.0 mg, 5.9 mg, 5.8 mg, 5.7 mg, 5.6 mg, 5.5 mg, 5.4 mg, 5.3 mg, 5.2 mg, 5.1 mg, 5.0 mg, 4.9 mg, 4.8 mg, 4.7 mg, 4.6 mg, 4.5 mg, 4.4 mg, 4.3 mg, 4.2 mg, 4.1 mg, 4.0 mg, 3.9 mg, 3.8 mg, 3.7 mg, 3.6 mg, 3.5 mg, 3.4 mg, 3.3 mg, 3.2 mg, 3.1 mg, 3.0 mg, 2.9 mg, 2.8 mg, 2.7 mg, 2.6 mg, 2.5 mg, 2.4 mg, 2.3 mg, 2.2 mg, 2.1 mg, 2.0 mg, 1.9 mg, 1.8 mg, 1.7 mg, or 1.7 mg daily. Administer daily doses of free base at doses of 1 mg, 1.6 mg, 1.5 mg, 1.4 mg, 1.3 mg, 1.2 mg, 1.1 mg, or 1.0 mg.

In some embodiments, compound 1 is administered at a daily dose of 2.6 to 3.0 mg, 1.6 to 2.0 mg, 0.6 to 1.0 mg, or 5.8 to 6.2 mg of free base. In some embodiments, compound 1 is administered at a daily dose of 2.8 mg of free base. In some embodiments, compound 1 is administered at a daily dose of 1.8 mg of free base. In some embodiments, compound 1 is administered at a daily dose of 0.8 mg of free base. In some embodiments, compound 1 is administered at a daily dose of 6.0 mg of free base.

In some embodiments, compound 1 is administered twice daily (bid), with bid being an abbreviation meaning twice daily and commonly used in drug administration instructions.

In some embodiments, compound 1 is administered in a delivery dose of 0.4 to 3.1 mg of free base twice daily. In some embodiments, compound 1 is administered at doses of 0.4 mg twice daily, 0.45 mg twice daily, 0.5 mg twice daily, 0.6 mg twice daily, 0.65 mg twice daily, 0.7 mg twice daily, 0.75 mg twice daily, 0.8 mg twice daily, 0.85 mg twice daily, 0.9 mg twice daily, 0.95 mg twice daily, 1.0 mg twice daily, 1.05 mg twice daily, 1.1 mg twice daily, 1.15 mg twice daily, 1.2 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, 1.6 mg twice daily, 1.65 mg twice daily, 1.7 mg twice daily, 1.75 mg twice daily, and 1.8 mg twice daily. Dosage administration at doses of 1.85 mg twice daily, 1.9 mg twice daily, 2.0 mg twice daily, 2.05 mg twice daily, 2.1 mg twice daily, 2.15 mg twice daily, 2.2 mg twice daily, 2.25 mg twice daily, 2.3 mg twice daily, 2.35 mg twice daily, 2.4 mg twice daily, 2.45 mg twice daily, 2.5 mg twice daily, 2.55 mg twice daily, 2.6 mg twice daily, 2.7 mg twice daily, 2.75 mg twice daily, 2.8 mg twice daily, 2.85 mg twice daily, 2.9 mg twice daily, 2.95 mg twice daily, 3.0 mg twice daily, 3.05 mg twice daily, or 3.1 mg twice daily. These doses refer to the dosage of free base.

In some embodiments, compound 1 is administered at doses of at least 0.4 mg twice daily, 0.45 mg twice daily, 0.5 mg twice daily, 0.6 mg twice daily, 0.65 mg twice daily, 0.7 mg twice daily, 0.75 mg twice daily, 0.8 mg twice daily, 0.85 mg twice daily, 0.9 mg twice daily, 0.95 mg twice daily, 1.0 mg twice daily, 1.05 mg twice daily, 1.1 mg twice daily, 1.15 mg twice daily, 1.2 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, 1.6 mg twice daily, 1.65 mg twice daily, 1.7 mg twice daily, 1.75 mg twice daily, and 1.8 mg twice daily. Dosage administration at doses of 1.85 mg twice daily, 1.9 mg twice daily, 2.0 mg twice daily, 2.05 mg twice daily, 2.1 mg twice daily, 2.15 mg twice daily, 2.2 mg twice daily, 2.25 mg twice daily, 2.3 mg twice daily, 2.35 mg twice daily, 2.4 mg twice daily, 2.45 mg twice daily, 2.5 mg twice daily, 2.55 mg twice daily, 2.6 mg twice daily, 2.7 mg twice daily, or 2.75 mg twice daily. These dosages refer to the dosage of free base.

In some embodiments, compound 1 is administered at doses of up to 3.1 mg twice daily, 3.05 mg twice daily, 3.0 mg twice daily, 2.95 mg twice daily, 2.9 mg twice daily, 2.85 mg twice daily, 2.8 mg twice daily, 2.75 mg twice daily, 2.7 mg twice daily, 2.65 mg twice daily, 2.6 mg twice daily, 2.55 mg twice daily, 2.5 mg twice daily, 2.45 mg twice daily, 2.4 mg twice daily, 2.35 mg twice daily, 2.3 mg twice daily, 2.25 mg twice daily, 2.2 mg twice daily, 2.15 mg twice daily, 2.1 mg twice daily, 2.05 mg twice daily, 2.0 mg twice daily, 1.95 mg twice daily, 1.9 mg twice daily, 1.85 mg twice daily, 1.8 mg twice daily, 1.75 mg twice daily, etc. Dosage options include: 1.7 mg twice daily, 1.65 mg twice daily, 1.6 mg twice daily, 1.55 mg twice daily, 1.5 mg twice daily, 1.45 mg twice daily, 1.4 mg twice daily, 1.35 mg twice daily, 1.3 mg twice daily, 1.25 mg twice daily, 1.2 mg twice daily, 1.15 mg twice daily, 1.1 mg twice daily, 1.05 mg twice daily, 1.0 mg twice daily, 0.95 mg twice daily, 0.9 mg twice daily, 0.85 mg twice daily, 0.8 mg twice daily, 0.75 mg twice daily, 0.7 mg twice daily, 0.65 mg twice daily, 0.6 mg twice daily, 0.55 mg twice daily, or 0.5 mg twice daily. These dosages refer to the dosage of free base. In some embodiments, the above-mentioned dosage of the active pharmaceutical ingredient is provided in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt delivered is linaloate.

In some embodiments, compound 1 is administered at a dose of 1.3 to 1.5 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 0.8 to 1.0 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 1.0 to 1.3 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 0.3 to 0.5 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 0.5 to 0.8 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 1.5 to 1.8 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 1.8 to 2.1 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 2.1 to 2.4 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 2.4 to 2.7 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 2.7 to 2.9 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 2.9 to 3.1 mg of free base twice daily. In some embodiments, compound 1 is administered as a delivery dose of 1.4 mg of free base twice daily.

In some embodiments, compound 1 is administered at a dose of 0.9 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 0.4 mg of free base twice daily. In some embodiments, compound 1 is administered at a dose of 3.0 mg of free base twice daily.

In some embodiments, the above-mentioned dosage of the active pharmaceutical ingredient is provided in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt delivered is xinarate.

In some embodiments, compound 1 is administered in the form of a pharmaceutically acceptable salt at a dose of about 0.4 to about 3.0 mg of the active drug twice daily. In some embodiments, the pharmaceutically acceptable salt is sine naphthol.

In some embodiments, the above-mentioned dosage of the active pharmaceutical ingredient is provided in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt delivered is xinarate.

In some embodiments, compound 1 is administered as a sine barium sulfate at a daily dose of 1.05 mg to 8.14 mg. In some embodiments, compound 1 is administered twice daily at a dose of approximately 1.69–1.99 mg of sine barium sulfate. In some embodiments, compound 1 is administered twice daily at a dose of 1.84 mg of sine barium sulfate. In some embodiments, compound 1 is administered twice daily at a dose of approximately 1.03 to 1.33 mg of sine barium sulfate. In some embodiments, compound 1 is administered twice daily at a dose of 1.18 mg of sine barium sulfate. In some embodiments, the sennarate of compound 1 is administered in a delivery dose of about 0.38 to 0.68 mg of sennarate twice daily. In some embodiments, the sennarate of compound 1 is administered in a delivery dose of 0.53 mg of sennarate twice daily.

In some embodiments, compound 1 is administered at a dose of approximately 3.7 to 4.1 mg of xinarate twice daily. In some embodiments, compound 1 is administered at a dose of 3.94 mg of xinarate twice daily.

The weight equivalent of compound 1 as the free base in 1.84 mg of xinarate salt is calculated to be approximately 1.4 mg (i.e., approximately 76% of the weight of xinarate in compound 1 corresponds to the free base, and the remaining approximately 24% corresponds to the salt).

The weight equivalent of compound 1 as the free base in 1.18 mg of xinarate salt is calculated to be approximately 0.9 mg (i.e., approximately 76% of the weight of xinarate in compound 1 corresponds to the free base, and the remaining approximately 24% corresponds to the salt).

The weight equivalent of compound 1 as the free base in 0.53 mg of xinarate salt is calculated to be approximately 0.4 mg (i.e., approximately 76% of the weight of xinarate in compound 1 corresponds to the free base, and the remaining approximately 24% corresponds to the salt).

The weight equivalent of compound 1 as the free base in 3.94 mg of xinarate salt is calculated to be approximately 3.0 mg (i.e., approximately 76% of the weight of compound 1 xinarate corresponds to the free base, and the remaining approximately 24% corresponds to the salt).

In some embodiments, the dosage listed is for dry powder inhalers.

In some embodiments, the listed dosages are unit doses dispensed from the inhaler. Therefore, these dosages are doses delivered from the inhaler. In some embodiments, the listed dosages are doses delivered from a dry powder inhaler. Method

The terms “treat,” “treating,” and “treatment” include inhibiting JAK1 in an individual, improving one or more symptoms of a disease or disorder in which JAK1 inhibition is beneficial in the individual, or slowing or delaying the progression of a disease or disorder in which JAK1 inhibition is beneficial in the individual.

The term "prevention" includes suppressing JAK1 in an individual to prevent or protect them from diseases or disorders that are beneficial to JAK1 suppression.

The terms "inhibit," "inhibition," or "inhibiting" encompass the reduction of the baseline activity of a biological activity or process.

The term "individual" refers to a human being. In some implementations, JAK1 inhibition in an individual is a beneficial disease or ailment.

In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered during the treatment cycle. In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered continuously during the treatment cycle.

The term "continuous" or "intermittently" refers to the administration of a treatment, such as compound 1, at regular intervals without stopping or interrupting it; that is, there are no ineffective days. An "ineffective day" refers to a day on which the treatment was not administered.

As used herein, “cycle,” “treatment cycle,” or “dosage schedule” refers to a treatment period repeated according to a regular timetable. For example, treatment may be administered for one, two, or three weeks, during which compound 1 is administered. In some practices, the treatment cycle is approximately one week to approximately three months. In some practices, the treatment cycle is approximately five days to approximately one month. In some practices, the treatment cycle is approximately one week to approximately three weeks. In some practices, the treatment cycle is approximately one week, approximately ten days, approximately two weeks, approximately three weeks, approximately four weeks, approximately two months, or approximately three months.

Phosphorylation of STAT6 in CD3+ T cell populations can be used as a marker of systemic exposure to compound 1. The determination of STAT6 phosphorylation (pSTAT6) can be performed using any suitable method known to those skilled in the art. For example, after administration of compound 1 to an individual, whole blood can be collected from the individual and stimulated with IL-4 and pSTAT6 in a CD3+ T cell subset assessed using fluorescence activated cell sorting (FACS). The inhibition of IL-4-stimulated STAT6 phosphorylation in CD3+ T cells after administration of compound 1 indicates systemic exposure to compound 1. The percentage of inhibition of IL-4-stimulated STAT6 phosphorylation in CD3+ T cells by compound 1 can be determined, for example, relative to a control individual who has not been administered any compound 1. This could be in the same individual (where IL-4-stimulated STAT6 phosphorylation in CD3+ T cells was evaluated prior to administration of compound 1) or in a different individual that had not yet been administered any compound 1.

The fractional concentration of exhaled nitric oxide (FeNO) can be used as a marker to determine the effectiveness of compound 1 in the treatment of asthma. Those familiar with this technique will be able to easily measure FeNO using known techniques, such as by slowly and steadily exhaling into the mouthpiece attached to a handheld monitor. The reading is displayed on the monitor, and the FeNO test result indicates the degree of airway inflammation. A commonly used FeNO test is the American Thoracic Society (ATS) 2005 test.

The percentage reduction in FeNO by compound 1 can be determined, for example, relative to a control individual who has not been given any compound 1. This can be in the same individual (where FeNO was evaluated before administration of compound 1) or in a different individual who has not been given any compound 1. A placebo may have been administered to this different individual.

In some embodiments, compound 1 is used to treat JAK1-related conditions. JAK1-related conditions include, for example, type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis arthritis, juvenile idiopathic arthritis, axial spondylitis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata.

In some implementations, the JAK1-related condition to be treated is asthma. In some implementations, the JAK1-related condition to be treated is mild asthma. In some implementations, the asthma is mild and occurs in patients with elevated FeNO levels.

In some implementations, the JAK1-related condition to be treated is COPD.

In some embodiments, compound 1 is used to treat asthma patients who still have symptoms despite treatment with medium to high doses of ICS-LABA.

In some embodiments, a method for treating or preventing asthma is disclosed, comprising administering compound 1 to an individual at a daily dose of 0.8 mg to 6.2 mg of free base, wherein compound 1 may be in the form of a pharmaceutically acceptable salt.

In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is disclosed for the treatment or prevention of asthma, wherein the treatment comprises administering compound 1 to the individual at a daily dose of 0.8 mg to 6.2 mg of free base.

In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof is disclosed for the manufacture of a medicine for the treatment or prevention of asthma, wherein the treatment comprises administering compound 1 to a patient at a daily dose of 0.8 mg to 6.2 mg of free base.

In some embodiments, a method for treating or preventing COPD is disclosed, comprising administering compound 1 to an individual at a daily dose of 0.8 mg to 6.2 mg of free base, wherein compound 1 may be in the form of a pharmaceutically acceptable salt.

In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is disclosed for the treatment or prevention of COPD, wherein the treatment comprises administering compound 1 to the individual at a daily dose of 0.8 mg to 6.2 mg of free base.

In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof is disclosed for the manufacture of a medicament for the treatment or prevention of COPD, wherein such treatment comprises administering compound 1 to a patient at a daily dose of 0.8 mg to 6.2 mg of free base . Preclinical studies

Safety and tolerability information from preclinical toxicology studies is summarized below: Inhalation of compound 1-cinnaric acid was tolerated in rats (up to 6 months) and dogs (up to 9 months). Decreased respiratory rate and tidal volume were observed in rats, but not in dogs. Pathological changes consistent with irritation were observed in the respiratory tract at dose levels higher than those used clinically. In the 9-month toxicology study, infection was detected in several dogs at the highest dose levels tested; however, no infection occurred at lower dose levels, at which the systemic exposure achieved was greater than the expected clinical exposure. *** Example 1 - Phase 1 Clinical Trial Parts 1a and 1b Phase 1

This study investigated the safety and preliminary clinical efficacy of compound 1 in patients with asthma. Part 1 was the first human clinical study evaluating the safety, tolerability, and single-dose pharmacokinetics of inhaled compound 1 in healthy volunteers. A total of 54 healthy participants were exposed to compound 1 at doses ranging from 0.3 to 6 mg (as a single dose), and 18 healthy participants were exposed to compound 1 at doses ranging from 0.4 to 3 mg BID (as multiple doses). In these healthy participants, compound 1 was found to be safe and well-tolerated. Figure 8 illustrates the Phase 1 (part 1a (SAD) and part 1b (oral and IV)) clinical trials, using the following abbreviations: DPI - dry powder inhaler, IV - intravenous, PO - oral, SAD - single escalator dose, SRC - Safety Review Committee. Part 1a

Part 1a involved single-dose administration of compound 1 via a dry powder inhaler in escalating doses. Seven dose levels of compound 1 (0.025 mg, 0.1 mg, 0.3 mg, 1 mg, 2 mg, 4 mg, and 6 mg) were investigated. Two subjects in the sentinel subgroup were administered each escalating dose group, with one subject receiving compound 1 and the other receiving a placebo. Subjects received a single inhaled dose of compound 1 or the corresponding placebo on day 1.

Summary of adverse events (AEs) in Part 1a: ▪ Headache (10 events) was the most frequently reported AE in subjects administered compound 1. ▪ The number of reported AEs for all other AEs was less than 3. ▪ The number of reported AEs for subjects administered the placebo was less than 3. No deaths or SAEs were reported. ▪ At least one AE was reported in 23 subjects (53.5%) administered compound 1 and 7 subjects (50.0%) administered the placebo. ▪ Overall, the investigators considered all reported AEs to be mild or moderate in intensity, except for one subject who experienced syncope on day 11, which the investigators considered to be of severe intensity. Subjects were administered 0.3 mg of compound 1. Part 1b

In Part 1b, compound 1 was administered to two different cohorts of healthy volunteers as a single intravenous (IV) or oral (PO) dose. The primary objective was to compare the pharmacokinetic (PK) ratios of IV, oral, and inhaled administration. Part 1b was an open-label, single-dose study consisting of two dose cohorts. Subjects received a single intravenous (IV) (0.3 mg) or oral (PO [oral]) (1 mg) dose of compound 1 on day 1. Administration in the IV and PO cohorts was performed by sentinel subjects. Dosage in the intravenous and oral cohorts...

The dose for group IV was 0.3 mg. The IV dose was selected based on a sufficiently high dose to allow for quantification of plasma compound 1 levels 24 hours post-dose using PK predictions (derived from preclinical PK). The dose was also selected to be sufficiently low to not exceed predefined exposure safety limits. The predicted exposure from a single IV dose was well below the maximum permissible exposure (1.7% of Cmax, 1.2% of AUC(0–24)).

The PO group dose was 1 mg. The PO dose was selected based on a sufficiently high dose to allow for quantification of plasma compound 1 levels 24 hours post-dose using PK predictions (derived from preclinical PK). The dose was also selected to be sufficiently low to not exceed predefined exposure safety limits. The predicted exposure from a single PO dose was well below the maximum permissible exposure (3.2% of Cmax and 3.1% of AUC(0-24)).

Summary of Adverse Events in Part 1b: • No deaths or SAEs were reported. • Slightly more AEs (5 AEs) were reported in subjects administered compound 1 0.3 mg IV than in subjects administered compound 1 1 mg PO (2 AEs). • Overall, the investigators considered all reported AEs to be mild or moderate in intensity. Objectives and Outcome Measures - Part 1a Table 1 - Primary Objectives and Outcome Measures for Phase 1 Part 1a Main objectives Result measurement To evaluate the safety and tolerability of compound 1 after inhalation of a single escalating dose to healthy volunteers. • Incidence of adverse events; • Vital signs (supine blood pressure, pulse, respiratory rate, and body temperature); • 12-lead electrocardiogram (ECG); • 12-lead digital electrocardiogram (dECG); • Telemetry; • Physical examination; • Laboratory assessments (hematology, clinical chemistry, and urinalysis); • Vital capacity measurement; • End-tidal _CO2 ; • Capillary blood gas; and • Oxygen saturation _SpO2 (peripheral capillary oxygen saturation). Table 2 - Partial Secondary Objectives and Results Measurements for Phase 1a Secondary objectives Result measurement To characterize the plasma p-value of compound 1 after a single escalation dose of inhaled compound 1. PK concentration and PK parameters: • Cmax (maximum observed plasma concentration), • Tmax (time to reach maximum observed concentration after drug administration), • λz (terminal elimination rate constant, estimated by linear regression from the end of the logarithmic concentration-time curve), • t½λz (half-life related to the terminal slope (λz) of the half-logarithmic concentration-time curve), • AUC(0-12) of the plasma concentration-time curve from time 0 to 12 hours, • AUC(0-24) of the plasma concentration-time curve from time 0 to 24 hours, • AUClast of the plasma concentration curve from zero to the last quantifiable concentration, • The area under the plasma concentration-time curve from zero to infinity (AUCinf) represents the total drug exposure over time. • CL/F: Apparent systemic clearance of the drug from plasma after epidural administration and subsequent administration; • Distribution volume (apparent) at steady state after epidural administration (based on end-stage) Vz/F; • AUClast/D - Dose-normalized AUClast, obtained by dividing AUClast by the administered dose; • AUCinf/D - Dose-normalized AUCinf, obtained by dividing AUCinf by the administered dose; • Cmax/D - Dose-normalized Cmax, obtained by dividing Cmax by the administered dose; • Time to last observed (quantifiable) concentration (tlast). Table 3 - Partial Exploratory Objectives and Results Measurements for Phase 1, Year 1 Exploratory goals Result measurement To study Ig (immunoglobulin) concentration Total Ig (immunoglobulins), Total IgE (immunoglobulin E) To evaluate the taste of compound 1 after inhalation of a single escalating dose to healthy volunteers. Standardized taste questionnaire Exposure-response (ER) analysis can be performed on heart rate-corrected QT (ECG interval measured from the start of the QRS complex to the end of the T wave) data from this study, either alone or in combination with other study portfolios as appropriate, using a pre-specified workflow for the QTc (heart rate-corrected QT interval) parameter as described in a separate technical document, as part of a cardiac safety assessment and intended to provide an alternative to TQT (comprehensive QT) studies. Dynamic electrocardiogram (dECG) Assessment of whole-body target adhesion Peripheral interleukin-4 (IL-4)-induced phosphorylation of STAT6 (signal transducer and transcription activator 6) To investigate the presence of metabolites of compound 1 in plasma The analysis will examine plasma samples for the presence of any metabolites. The results will guide future studies on exposure to metabolites of compound 1. To evaluate the effect of compound 1 on cough frequency in healthy volunteers compared to a placebo. Cough frequency monitoring Part 1b Table 4 - Phase 1 Part 1b (IV or PO Dosage) Key Objectives and Outcome Measures Main objectives Result measurement To characterize the plasma p-value of compound 1 after a single intravenous and post-oral administration of a single dose to healthy volunteers. PK concentration and PK parameters: • Cmax (maximum observed plasma concentration), • Tmax (time to reach maximum observed concentration after drug administration), • λz (terminal elimination rate constant, estimated by linear regression from the end of the logarithmic concentration-time curve), • t½λz (half-life associated with the terminal slope (λz) of the half-logarithmic concentration-time curve), • AUC(0-12) of the plasma concentration-time curve from time 0 to 12 hours, • AUC(0-24) of the plasma concentration-time curve from time 0 to 24 hours, • AUClast of the plasma concentration curve from zero to the last quantifiable concentration, • The area under the plasma concentration-time curve from zero to infinity (AUCinf) represents the total drug exposure over time. • CL/F: Apparent systemic clearance of the drug from plasma after epidural administration and subsequent administration; CL: Systemic clearance of the drug from plasma after intravenous administration and subsequent administration; • CL: Systemic clearance of the drug from plasma after intravenous administration and subsequent administration; • Volume of distribution (apparent) at steady state after epidural administration and subsequent administration (based on end-stage) Vz/F; • Vz: Volume of distribution after intravenous administration and subsequent administration (based on end-stage); • AUClast/D - Dose-normalized AUClast, obtained by dividing AUClast by the administered dose; • AUCinf/D - Dosage normalization AUCinf, obtained by dividing AUCinf by the dose administered; • Cmax/D, dosage normalization Cmax, obtained by dividing Cmax by the dose administered; • Time to finally observe (quantifiable) concentration (tlast). Table 5 - Secondary objectives and outcome measures for Phase 1, Part 1b (IV or PO dose) Secondary objectives Result measurement To evaluate the safety and tolerability of compound 1 after intravenous and PO administration to healthy volunteers. • Incidence of adverse events, • Vital signs (supine blood pressure, pulse, respiratory rate, and body temperature), • 12-lead electrocardiogram (ECG), • 12-lead digital electrocardiogram (dECG), • Telemetry, • Physical examination, • Laboratory assessments (hematology, clinical chemistry, and urinalysis), • End-tidal _CO2 , To evaluate the renal clearance of compound 1 after a single IV administration to healthy volunteers. Where possible, the following pharmacokinetic parameters will be evaluated: CLR (renal clearance from plasma), fe(t1-t2) - the cumulative percentage of the constant dose excreted in urine from time t1 to time t2, and Ae(t1-t2) - the cumulative amount of the constant drug excreted in urine from time t1 to time t2. Table 6 - Phase 1 Part 1b (IV or PO Dosage) Exploratory Objectives and Result Measures Exploratory goals Result measurement To study Ig concentration Total Ig (immunoglobulins), Total IgE (immunoglobulin E) Exposure-response (ER) analysis can be performed on heart rate-corrected QT (ECG interval measured from the start of the QRS complex to the end of the T wave) data from this study, either alone or in combination with other study portfolios as appropriate, using a pre-specified workflow for the QTc (heart rate-corrected QT interval) parameter as described in a separate technical document, as part of a cardiac safety assessment and intended to provide an alternative to TQT (comprehensive QT) studies. Dynamic electrocardiogram (dECG) Partial PK data of 1a

Compound 1 was found to be rapidly absorbed following a single dose, with a median tmax ranging from 0.07 to 0.14 hours post-dose. Plasma concentration decreased rapidly to 0.5 hours post-dose after Cmax. t½λz was consistent between 28.6 and 31.0 hours. No dose-dependent effect on pharmacokinetic activity was observed within the 1 to 6 mg dose range. Inter-subject variability based on geometric CV was also found to be within the 21.0% to 79.0% range for Cmax and within the 13.0% to 45.1% range for AUC(0–24).

The PK data for part 1a is shown in Table 7: Table 7 - PK data for Day 1 of Part 1a. Day 1 of the PK Compound 1 DPI dosage Parameters ( units) Statistics 0.025 mg (N = 6) 0.1 mg (N = 6) 0.3 mg (N = 7) 1 mg (N = 6) AUCinf (h*nmol/L) Geometric Mean (CV%) Min - Max [n] NC NC 3.656 (17.73) 2.87 - 4.64 [6] 17.17 (15.53) 14.0 - 20.9 [7] 73.15 (16.95) 60.0-90.6 [6] AUC(0-12) (h*nmol/L) Geometric mean (CV%) Min - Max [n] NC NC 1.612 (14.29) 1.38 -1.95 [6] 5.107 (15.18) 4.07 - 6.28 [7] 18.48 (32.30) 13.3 - 28.4 [6] AUC(0-24) (h*nmol/L) Geometric Mean (CV%) Min - Max [n] NC NC 2.521 (14.78) 2.08 - 3.02 [6] 8.359 (14.10) 6.91 - 9.88 [7] 31.06 (30.11) 22.8 - 46.6 [6] AUClast (h*nmol/L) Geometric Mean (CV%) Min - Max [n] NC NC 1.474 (31.17) 1.02 - 2.38 [6] 12.40 (15.69) 10.3 -15.3 [7] 60.09 (24.02) 45.1 - 79.5 [6] Cmax (nmol/L) Geometric Mean (CV%) Min - Max [n] 0.2015 (23.19) 0.164 - 0.253 [4] 0.6519 (36.18) 0.394 - 1.11 [6] 2.205 (79.04) 1.33 - 7.23 [7] 4,979 (48.45) 2.25 - 7.87 [6] tmax(h) Median (Min - Max) [n] 0.08 0.07 - 0.08 [4] 0.08 0.07 - 0.10 [6] 0.08 0.07 - 0.13 [7] 0.08 0.05 - 0.10 [6] t½λz (h) Geometric Mean (CV%) Min - Max [n] NC NC 13.62 (13.75) 11.2 - 15.9 [6] 25.12 (13.39) 19.2 - 29.0 [7] 31.03 (25.63) 22.5 - 43.4 [6] CL/F (L/h) Geometric Mean (CV%) Min - Max [n] NC NC 45.62 (17.73) 35.9 - 58.2 [6] 29.15 (15.53) 23.9 - 35.8 [7] 22.80 (16.95) 18.4 - 27.8 [6] VzF (L) Geometric Mean (CV%) Min Max [n) NC NC 896.6 (12.80) 739 - 1080 [6] 1056 (13.85) 901 - 1320 [7] 1020 (39.12) 597 - 1430 [6] Day 1 of the PK Compound 1 DPI dosage Parameters ( units) Statistics 2 mg (N = 6) 4 mg (N = 6) 6 mg (N = 6) AUCinf (h*nmol/L) Geometric mean (CV%) Min - Max [n] 123.6 (42.81) 67.6 - 183 [6] 254.1 (25.74) 193 - 349 [6] 355.1 (22.20) 244 - 450 [6] AUC(0-12) (h*nmol/L) Geometric Mean (CV%) Min - Max [n] 31.86 (48.98) 13.8 - 46.6 [6] 67.66 (23.12) 49.3 - 85.7 [6] 104.2 (9.221) 91.6 - 119 [6] AUC(0-24) (h*nmol/L) Geometric mean (CV%) Min - Max [n] 53.88 (45.11) 25.1 - 77.6 [6] 114.6 (21.85) 85.8 - 147 [6] 172.0 (13.03) 138 - 202 [6] AUClast (h*nmol/L) Geometric mean (CV%) Min - Max [n] 116.6 (44.41) 61.6 - 173 [6] 243.7 (24.47) 188 - 324 [6] 343.0 (20.87) 239 - 422 [6] Cmax (nmol/L) Geometric mean (CV%) Min - Max [n] 10.48 (58.51) 3.69 - 17.6 [6] 18.78 (46.55) 11.3 - 31.5 [6] 21.09 (20.95) 16.6 - 25.6 [6] tmax (h) Median (Min - Max) [n] 0.07 0.05 - 0.10 [6] 0.12 0.10 - 0.12 [6] 0.14 0.10 - 0.28 [6] t½λz (h) Geometric Mean (CV%) Min - Max [n] 31.01 (13.38) 23.7 - 33.7 [6] 29.15 (21.48) 21.7 - 37.9 [6] 28.62 (14.17) 24.9 - 35.1 [6] CL/F (L/h) Geometric mean (CV%) Min - Max [n] 26.98 (42.81) 18.3 - 49.3 [6] 26.25 (25.74) 19.1 - 34.6 [6] 28.17 (22.20) 22.2 - 41.1 [6] VzF (L) Geometric Mean (CV%) Min Max [n) 1207 (39.68) 849 - 2390 [6] 1104 (20.78) 869 - 1520 [6] 1163 (14.67) 973 - 1480 [6] SAD: Single escalation dose; DPI: Dry powder inhaler; N: Number of subjects in the pharmacokinetic pool; n: Number of subjects in the analysis; Geoman: Geometric mean; Max: Maximum value; Min: Minimum value; CV: Coefficient of variation (%); NC: Not calculated

This data is also shown in Figure 1, where: Dosage 0.1 mg 0.3 mg 1 mg 2 mg 4 mg 6 mg symbols ● ○ Ɪ £ ▽ ó Partial 1b PK data

Following 0.3 mg IV and 1 mg oral administration, the geometric mean t½λz for compound 1 was 23.8 hours and 30.6 hours, respectively. In the IV group, 3/6 of the t½λz values in the oral group and all t½λz values were calculated over a period less than three times the obtained half-life; therefore, terminal phase may not be fully represented in these groups. Despite different PK collection time points, the geometric mean t½λz values were similar among the IV, oral, and inhaled (partial 1a SAD 1 to 6 mg range: 28.6 to 31.0 hours) groups, indicating consistent elimination of compound 1 across the three dosage routes. The estimated possible oral bioavailability of compound 1 based on the geometric mean AUCinf value is 36.0%. The inter-subject variability in geometric CV based on IV and oral administration was 42.9% and 44.1% for Cmax, respectively, and 17.4% and 38.1% for AUC(0-24), respectively.

Following a single IV dose of 0.3 mg of compound 1, the excretion of compound 1 in urine was low, with an arithmetic mean percentage of excretion [fe(0-48)] of 8.25% and an arithmetic mean CLR of 1.77 L/h.

Partial PK data for 1b is shown in Tables 8 and 9 below. Table 8 - Partial PK Day 1 Data for 1b Day 1 of the PK Compound 1 dosage Parameters ( units) Statistics 0.3 mg IV (N=6) 1 mg orally (N = 6) AUCinf (h*nmol/L) Geometric mean (CV%) Min-Max [n] 30.80 (12.29) 25.3 - 36.7 [6] 36.98 (33.70) 21.9 – 50.5 [6] AUC(0-12) (h*nmol/L) Geometric mean (CV%) Min-Max [n] 11.14 (18.77) 8.41 - 14.2 [6] 8.310 (43.98) 4.90 – 13.8 [6] AUC(0-24) (h*nmol/L) Geometric mean (CV%) Min-Max [n] 16.49 (17.37) 13.0 – 20.3 [6] 14.86 (38.12) 9.37 – 23.1 [6] AUClast (h*nmol/L) Geometric mean (CV%) Min-Max [n] 23.35 (14.82) 19.7 – 28.9 [6] 26.66 (39.04) 15.1 – 40.0 [6] Cmax (nmol/L) Geometric mean (CV%) Min-Max [n] 7.577 (42.88) 3.50 – 11.1 [6] 0.8609 (44.07) 0.554 – 1.48 [6] tmax (h) Geometric mean (CV%) Min-Max [n] 0.33 0.27 – 0.37 [6] 4.51 1.48 – 8.00 [6] t½λz (h) Geometric mean (CV%) Min-Max [n] 23.78 (24.73) 18.3 – 32.4 [6] 30.59 (39.82) 22.3 – 65.1 [6] CL/F or CL (L/h) Geometric mean (CV%) Min-Max [n] 16.24 (12.29) 13.6 – 19.8 [6] 45.10 (33.70) 33.0 – 76.2 [6] Vz/F or Vz (L) Geometric mean (CV%) Min-Max [n] 557.2 (26.40) 414 – 761 [6] 1990 (43.18) 1180 – 3100 [6] DPI: Dry powder inhaler; IV: Intravenous; N: Number of subjects in the pharmacokinetic analysis set; n: Number of subjects included in the analysis; Geoman: Geometric mean; Max: Maximum value; Min: Minimum value; CV: Coefficient of variation (%)

This data for Day 1 is also shown in Figure 2, where: Dosage 0.3 mg 1 mg symbols ○ Ɪ

Following a single IV dose of 0.3 mg of compound 1, urinary excretion of compound 1 was low, with an arithmetic mean percentage of excretion [fe(0-48)] of 8.25% and an arithmetic mean CLR of 1.77 L/h. Table 9 - Partial PK Day 1 data for 1b Parameters (units) Statistics 0.3 mg IV compound 1 (N = 6) fe(0-48) (%) Arithmetic mean (SD) Geometric mean (CV%) Min-Max [n] 8.249 (1.710) 8.087 (22.73) 5.54-10.1 [6] CLR(0-48) (L/h) Arithmetic mean (SD) Geometric mean (CV%) Min-Max [n] 1.773 (0.4245) 1.735 (22.47) 1.41-2.51 [6] IV: Intravenous; N: Number of subjects in the pharmacokinetic analysis set; n: Number of subjects included in the analysis; SD: Standard deviation; CV: Coefficient of variation (%); Max: Maximum value; min: Minimum value . Example 2 - Phase 1 Clinical Trial Parts 2 and 3. Phase 1 Clinical Trial Part 2

Once at least four cohorts in Part 1a (SAD) have been completed, Part 2 (Multiple Escalating Dosage [MAD]) begins. In Part 2 (MAD), Compound 1 is administered to healthy volunteers at multiple doses (twice daily [BID], 7 days). Safety, tolerability, and multiple-dose pharmacokinetics will be examined in Part 2. Compound 1, prepared in DPI form, will be administered at multiple doses. Part 2 is a randomized, single-blind, placebo-controlled, multiple escalating dose (MAD), sequential design. Three dose levels of Compound 1 will be studied (0.4 mg, 1.4 mg, and 3 mg). Two participants in each escalating dose cohort will be administered to each participant in the sentinel subgroup, resulting in one participant receiving Compound 1 and one participant receiving a placebo. Subjects received either compound 1 or a placebo twice daily (BID) from day 1 to day 6 (with a 12-hour [± 30 min] interval between doses), and a single inhalation on day 7.

Figure 9 illustrates the Phase 1 Part 2 clinical trial, where N = x(y+z) represents the number of healthy volunteers, where x is the total number, y is the compound 1 code administered, and z is the number of placebo administered. The following abbreviations are used in Figure 9: DPI - dry powder inhaler, IV - intravenous, PO - oral, MAD - multiple escalation dose, SRC - safety review committee. Table 10 - Part 2 Primary Objectives and Result Measures Main objectives Result measurement To evaluate the safety and tolerability of compound 1 after inhalation with multiple escalating doses in healthy volunteers. • Incidence of adverse events; • Vital signs (supine blood pressure, pulse, respiratory rate, and body temperature); • 12-lead electrocardiogram (ECG); • 12-lead digital electrocardiogram (dECG); • Telemetry; • Physical examination; • Laboratory assessments (hematology, clinical chemistry, and urinalysis); • Lung capacity measurement; • Capillary blood gas and oxygen saturation SpO2 (peripheral capillary oxygen saturation). Table 11 - Partial Secondary Objectives and Outcome Measures for Phase 1 Secondary objectives Result measurement To characterize the plasma p-value of compound 1 after multiple escalation doses administered to healthy volunteers. PK concentration and PK parameters: • Cmax (maximum observed plasma concentration), • Tmax (time to reach maximum observed concentration after drug administration), • λz (terminal elimination rate constant, a linear regression estimate of the terminal portion of the logarithmic concentration-time curve), • t½λz (half-life associated with the terminal slope (λz) of the half-logarithmic concentration-time curve), • AUC(0-24) – area under the plasma concentration-time curve from time 0 to 24 hours, • AUCτ – area under the plasma concentration-time curve during dose intervals, • AUClast – area under the plasma concentration curve from zero to the last quantifiable concentration, • CL/F: Apparent systemic clearance of drug from plasma after extravasation and subsequent administration; • Volume of distribution (apparent) at steady state after extravasation and subsequent administration (based on end-stage) Vz/F; • AUClast/D - Dose-normalized AUClast, obtained by dividing AUClast by the administered dose; • AUCτ/D - Dose-normalized AUCτ, obtained by dividing AUCτ by the administered dose; • Cmax/D - Dose-normalized Cmax, obtained by dividing Cmax by the administered dose; • Rac AUC - Cumulative ratio of AUCτ; • Rac Cmax - Cumulative ratio of Cmax; • Time to last observed (quantifiable) concentration (tlast) To assess the effect of compound 1 on the severity of cough in healthy volunteers compared to a placebo. Self-assessment of cough severity Table 12 - Part 2 of Phase 1: Exploratory Objectives and Results Measurement Exploratory goals Result measurement To study Ig concentration Total Ig (immunoglobulins), Total IgE (immunoglobulin E) Exposure-response (ER) analysis can be performed on HR-corrected QT (ECG interval from the start of the QRS complex to the end of the T wave) data from this study, either alone or as appropriate, in combination with other study portfolios, using a pre-specified workflow for the QTc (heart rate-corrected QT interval) parameter as described in a separate technical document, as part of a cardiac safety assessment and intended to provide an alternative to TQT (comprehensive QT) studies. Dynamic electrocardiogram (dECG) To investigate the presence of metabolites of compound 1 in plasma and urine. The analysis was conducted to determine whether any metabolites were present in plasma and urine samples under steady-state conditions. To quantify 4-β-OH-cholesterol in plasma As a marker for CYP3A4 induction after repeated administration of compound 1 To evaluate the effect of compound 1 on cough frequency in healthy volunteers compared to a placebo. Cough frequency monitoring To assess the feasibility and subject acceptability of finger-prick self-sampling for the safety and pk concentration of compound 1 (optional). TDL Tinies self-collected samples

Summary of adverse events in Part 2: • No deaths or SAEs were reported. • At least one AE was reported in 13 subjects (72.2%) who received Compound 1 and 5 subjects (83.3%) who received the placebo. • Overall, the investigators considered all reported AEs to be mild or moderate in intensity. • For subjects who received Compound 1, most AEs were reported for SOC neurological disorders (9 AEs) and respiratory, chest, and mediastinal disorders (8 AEs). • The most frequently reported AEs in subjects who received Compound 1 were dizziness and cough (4 AEs each). • For subjects who received the placebo, most AEs were reported for SOC neurological disorders (3 AEs). • The most frequently reported AE in subjects who received the placebo was dizziness (2 AEs). • Researchers assessed that adverse events (AEs) reported by 11 (61.1%) subjects given compound 1 and 4 (66.7%) subjects given a placebo were likely related to IMP. • AEs reported by one or more subjects in different groups that researchers assessed as likely related to IMP included: • Dizziness (reported in 2 [33.3%] subjects given 0.4 mg and 3 mg of compound 1 and 1 [16.7%] subject given a placebo). • Headache (reported in 1 [16.7%] subject given 0.4 mg and 3 mg of compound 1 and 1 [16.7%] subject given a placebo). • Cough (reported in 2 subjects [33.3%] who received compound 1 3 mg and 1 subject [16.7%] who received a placebo). • Fatigue (reported in 2 subjects [33.3%] who received compound 1 0.4 mg, 1 subject [16.7%] who received compound 1 1.4 mg and 1 subject [16.7%] who received a placebo). Part 2 PK data

Following a single dose of 0.4 to 3 mg of compound 1 in a dry powder inhaler on day 1, partial pharmacokinetic data for compound 2 are shown in Figure 3, where: Dosage 0.4 mg 1.4 mg 3 mg symbols + # △

Consistent with part 1a, following a single dose of 0.4 to 3 mg DPI compound 1 on day 1, compound 1 is rapidly absorbed at a median tmax in the range of 0.08 to 0.10 hours post-dose.

Following multiple BID doses of compound 1 (0.4 to 3 mg) in a dry powder inhaler on day 7, partial pharmacokinetic data for compound 2 are shown in Figure 4, where: Dosage 0.4 mg 1.4 mg 3 mg symbols + # △

Consistent with the single-dose profile on Day 1 of the PK trial, following multiple BID doses of compound 1 at a median tmax ranging from 0.08 to 0.12 hours post-dose, compound 1 was rapidly absorbed. Quantifiable concentrations of compound 1 were observed in all subjects except one (0.4 mg BID group) up to the last 144-hour post-dose time point after multiple doses on Day 7. (Phase 1 Clinical Trial Part 3 )

Part 3 of the study was a randomized, single-blind, placebo-controlled, multiple-dose, pharmacokinetic, and PD study conducted in patients with mild asthma. Two dosage levels of compound 1 were studied (1.4 mg and 3 mg).

Subjects received either a BID inhaled dose of compound 1 or a placebo (12-hour intervals between doses) from day 1 to day 9, and a single inhaled dose on day 10.

Figure 10 illustrates the Phase 1 Part 3 clinical trial, using the following abbreviations: BID - twice daily; MAD - multiple escalation dose; PoM - proof of mechanism; SRC - Safety Review Committee. Table 13 - Phase 1 Part 3 Key Objectives and Result Measures Main objectives Result measurement To evaluate the safety and tolerability of compound 1 administered via multiple escalation doses after inhalation of a DPI to patients with mild asthma. • Incidence of adverse events; • Vital signs (supine blood pressure, pulse, respiratory rate, and body temperature); • 12-lead electrocardiogram (ECG); • 12-lead digital electrocardiogram (dECG); • Telemetry; • Physical examination; • Laboratory assessments (hematology, clinical chemistry, and urinalysis); • Lung capacity measurement; • Capillary blood gas and oxygen saturation _SpO2 (peripheral capillary oxygen saturation). Table 14 - Partial Three Secondary Objectives and Outcome Measures for Phase 1 Secondary objectives Result measurement To characterize the plasma p-value of compound 1 after administering multiple escalation doses of DPI to asthma patients. PK concentration and PK parameters include: • Cmax (maximum observed plasma concentration), • AUC - area of plasma concentration over time after administration • AUCτ - area of plasma concentration over time during dose intervals. To evaluate the effect of compound 1 on the severity of cough in patients with mild asthma. Self-Assessment of Cough Severity (VAS) To assess the anti-inflammatory effect in patients with mild asthma Changes in FeNO levels from baseline 2 hours after morning dose on days 1 to 10. Changes in FeNO levels from baseline before morning dose (days 1 to 9 and 10) and before evening dose on days 1 to 9. Table 15 - Partial Three Secondary Objectives and Outcome Measures for Phase 1 Exploratory goals Result measurement To study Ig concentration Total Ig (immunoglobulins), total IgE (immunoglobulin E), and specific IgE ER analysis of HR-corrected QT data from this study can be performed alone or, as appropriate, in combination with other studies, using a pre-specified workflow for QTc parameters described in a separate technical document, as part of a cardiac safety assessment and intended to provide an alternative to TQT studies. dECG (digital electrocardiogram) Assessment of whole-body target adhesion Peripheral IL-4-induced STAT6 phosphorylation (signal transducer and transcription activator 6) To evaluate plasma proteins and upper airway tissue biomarkers associated with asthma and the JAK1 pathway. Protein biomarkers in plasma (e.g., EDN (eosinophil-derived neurotoxin), CCL17 (interleukin (CC motif) ligand 17)). Protein biomarkers in nasal lining fluid (type 2 and non-type 2) obtained via nasal absorption Part 3 PK Data

The pharmacokinetic (PK) data of some compounds 3 after single doses of 1.4 and 3 mg of compound 1 in the DPI in patients with mild asthma on day 1 are shown in Figure 5. Dosage 1.4 mg 3 mg symbols # r

Consistent with parts 1a and 2, in patients with mild asthma, compound 1 was rapidly absorbed at tmax 0.07 and 0.08 hours after a single dose of 1.4 and 3 mg in the DPI.

The pharmacokinetic data of compound 3 after multiple BID doses of 1.4 and 3 mg of compound 3 in the DPI in patients with mild asthma on day 10 are shown in Figure 6. Dosage 1.4 mg 3 mg symbols # r

The time to t½λz following multiple BIDs was consistent between healthy volunteers and patients, with geometric mean values ranging from 37.2 to 39.0 hours in Part 2 and from 36.9 to 44.7 hours in Part 3. Generally, patients appeared to show lower exposure to Compound 1 compared to healthy volunteers.

The geometric mean Cmax of patients decreased by 35% after a single 3 mg dose and by 27% and 32% after multiple doses of 1.4 and 3 mg BID, respectively. In contrast, patients showed a 34% higher geometric mean Cmax than healthy volunteers at the 1.4 mg dose on day 1; however, inter-subject variability in Cmax of the 1.4 and 3 mg groups was unusually high in parts 2 and 3 of day 1 PK (58.1 to 80.7% geometric CV).

Compared with volunteers, patients also had lower geometric mean AUC, but to a lesser extent 12% and 26% lower from a single dose, and 7% and 18% lower after multiple doses of 1.4 and 3 mg BID, respectively.

The pharmacokinetic (PK) data for single doses of portions 2 and 3 are shown in the table below: Table 16 - Pharmacokinetic Data for Single Dose of Portions 2 and 3 Day 1 of the PK Part 2 of the healthy volunteers DPI compound 1 Parameters (units) Statistics 0.4 mg (N = 6) 1.4 mg (N = 6) 3 mg (N = 6) AUCτ (h*nmol/L) Geometric mean (CV%) Min-Max [n] 5.230 (37.09) 2.83 – 7.53 [6] 29.18 (35.41) 21.3 – 47.6 [6] 60.52 (20.89) 40.1 – 71.3 [6] AUClast (h*nmol/L) Geometric mean (CV%) Min-Max [n] 5.174 (36.99) 2.80 – 7.45 [6] 29.04 (35.18) 21.2 – 47.0 [6] 59.48 (20.36) 39.6 – 68.1 [6] Cmax (nmol/L) Geometric mean (CV%) Min-Max [n] 2.922 (56.34) 1.61 – 6.37 [6] 7.030 (80.67) 3.72 – 18.6 [6] 20.15 (78.69) 7.14 – 48.3 [6] tmax (h) Geometric mean (CV%) Min-Max [n] 0.08 0.07 – 0.13 [6] 0.10 0.07 – 0.12 [6] 0.09 0.08 – 0.13 [6] AUCτ/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 13.07 (37.09) 7.07 – 18.8 [6] 20.85 (35.41) 15.2 – 34.0 [6] 20.17 (20.89) 13.4 – 23.8 [6] AUClast/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 12.93 (36.99) 7.00 – 18.6 [6] 20.74 (35.18) 15.1 – 33.6 [6] 19.83 (20.36) 13.2 – 22.7 [6] Cmax/D (nmol/L/mg) Geometric mean (CV%) Min-Max [n] 7.304 (56.34) 4.01 – 15.9 [6] 5.022 (80.67) 2.66 – 13.3 [6] 6.716 (78.69) 2.38-16.1 [6] Day 1 of the PK Part 3 patients DPI compound 1 Parameters (units) Statistics 1.4 mg (N=6) 3 mg (N=7) AUCτ (h*nmol/L) Geometric mean (CV%) Min-Max [n] 25.54 (24.53) 17.9 – 34.9 [6] 44.90 (20.06) 35.7 – 65.0 [7] AUClast (h*nmol/L) Geometric mean (CV%) Min-Max [n] 25.53 (24.17) 18.0 – 34.9 [6] 44.89 (19.72) 36.0 – 64.8 [7] Cmax (nmol/L) Geometric mean (CV%) Min-Max [n] 9.399 (59.41) 4.88 – 17.7 [6] 13.07 (58.06) 6.42 – 34.6 [7] tmax (h) Geometric mean (CV%) Min-Max [n] 0.07 0.05 – 0.08 [6] 0.08 0.07 – 0.13 [7] AUCτ/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 18.24 (24.53) 12.8 – 24.9 [6] 14.97 (20.06) 11.9 -21.6 [7] AUClast/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 18.24 (24.17) 12.9 – 25.0 [6] 14.96 (19.72) 12.0 – 21.6 [7] Cmax/D (nmol/L/mg) Geometric mean (CV%) Min-Max [n] 6.714 (59.41) 3.48 – 12.7 [6] 4.356 (58.06) 2.14 – 11.5 [7] MAD: Multiple escalation dose; DPI: Dry powder inhaler; N: Number of subjects in the pharmacokinetic analysis set; n: Number of subjects included in the analysis; Geoman: Geometric mean; Max: Maximum value; Min: Minimum value; CV: Coefficient of variation (%)

The pharmacokinetic (PK) data for multiple doses of some 2 and 3 are shown in the table below: Table 17 - Pharmacokinetic data for multiple doses of some 2 and 3. PK Day 7 and Day 10* Part 2 of the healthy volunteers DPI compound 1 Parameters ( units) Statistics 0.4 mg BID (N = 6) 1.4 mg BID (N = 6) 3 mg BID (N = 6) AUCτ (h*nmol/L) Geometric mean (CV%) Min-Max [n] 24.50 (21.01) 18.2 – 30.9 [6] 118.3 (23.32) 86.9 – 158 [6] 235.5 (22.55) 165 – 295 [6] AUClast (h*nmol/L) Geometric mean (CV%) Min-Max [n] 98.58 (38.08) 52.0 – 135 [6] 499.8 (43.07) 315 – 847 [6] 987.9 (38.60) 608 – 1540 [6] Cmax (nmol/L) Geometric mean (CV%) Min-Max [n] 5.366 (30.81) 3.90 – 8.52 [6] 19.92 (16.41) 16.5 – 26.0 [6] 41.98 (23.94) 30.8 – 60.7 [6] tmax (h) Geometric mean (CV%) Min-Max [n] 0.08 0.07 – 0.12 [6] 0.08 0.07 – 0.10 [6] 0.12 0.07 -0.15 [6] t½λz (h) Geometric mean (CV%) Min-Max [n] 38.95 (21.24) 28.8 – 54.5 [6] 37.17 (19.46) 29.5 – 50.3 [6] 38.51 (19.22) 31.7 – 52.9 [6] CL/F (L/h) Geometric mean (CV%) Min-Max [n] 27.22 (21.01) 21.6 – 36.7 [6] 19.74 (23.32) 14.7 – 26.9 [6] 21.25 (22.55) 16.9 – 30.3 [6] Vz/F (L) Geometric mean (CV%) Min-Max [n] 1530 (24.44) 1190 – 2100 [6] 1059 (10.50) 866 – 1150 [6] 1180 (13.06) 987 – 1420 [6] Rac AUC Geometric mean (CV%) Min-Max [n] 4.685 (34.36) 3.44 – 8.83 [6] 4.052 (34.92) 2.27 – 6.46 [6] 3.891 (15.49) 3.18 – 4.59 [6] Rac Cmax Geometric mean (CV%) Min-Max [n] 1.837 (46.49) 0.911 – 2.87 [6] 2.834 (76.38) 1.37 – 5.42 [6] 2.084 (53.72) 1.26 – 4.95 [6] AUCτ/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 61.25 (21.01) 45.4 – 77.3 [6] 84.47 (23.32) 62.1 – 113 [6] 78.48 (22.55) 55.0 – 98.5 [6] AUClast/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 246.4 (38.08) 130 – 338 [6] 357.0 (43.07) 225 – 605 [6] 329.3 (38.60) 203 – 513 [6] Cmax/D (nmol/L/mg) Geometric mean (CV%) Min-Max [n] 13.41 (30.81) 9.75 – 21.3 [6] 14.23 (16.41) 11.8 – 18.6 [6] 13.99 (23.94) 10.3 – 20.2 [6] PK Day 7 and Day 10* Part 3 patients DPI compound 1 Parameters ( units) Statistics 1.4 mg BID (N = 6) 3 mg BID (N = 7) AUCτ (h*nmol/L) Geometric mean (CV%) Min-Max [n] 110.1 (10.26) 93.7 – 125 [6] 192.1 (25.65) 141 – 251 [6] AUClast (h*nmol/L) Geometric mean (CV%) Min-Max [n] 479.8 (26.81) 355 – 689 [6] 948.6 (32.74) 678 – 1410 [6] Cmax (nmol/L) Geometric mean (CV%) Min-Max [n] 14.64 (19.51) 11.3 – 19.6 [6] 28.37 (28.22) 20.2 – 46.5 [6] tmax (h) Geometric mean (CV%) Min-Max [n] 0.08 0.07 – 0.42 [6] 0.08 0.05 – 0.13 [6] t½λz (h) Geometric mean (CV%) Min-Max [n] 36.90 (22.08) 29.4 – 49.9 [6] 44.73 (21.07) 32.4 – 60.7 [6] CL/F (L/h) Geometric mean (CV%) Min-Max [n] 21.20 (10.26) 18.7 – 24.9 [6] 26.05 (25.65) 19.9 – 35.4 [6] Vz/F (L) Geometric mean (CV%) Min-Max [n] 1129 (14.72) 910 – 1340 [6] 1681 (34.29) 934 – 2320 [6] Rac AUC Geometric mean (CV%) Min-Max [n] 4.311 (30.22) 3.09 – 6.73 [6] 4.226 (18.23) 3.32 – 5.52 [6] Rac Cmax Geometric mean (CV%) Min-Max [n] 1.557 (58.01) 0.637 – 2.71 [6] 2.108 (39.22) 1.34 – 3.51 [6] AUCτ/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 78.66 (10.26) 66.9 – 89.2 [6] 64.02 (25.65) 47.1 – 83.6 [6] AUClast/D (h*nmol/L/mg) Geometric mean (CV%) Min-Max [n] 342.7 (26.81) 254 – 492 [6] 316.2 (32.74) 226 – 469 [6] Cmax/D (nmol/L/mg) Geometric mean (CV%) Min-Max [n] 10.45 (19.51) 8.06 – 14.0 [6] 9.456 (28.22) 6.74 – 15.5 [6] MAD: Multiple escalation dose; DPI: Dry powder inhaler; N: Number of subjects in the pharmacokinetic analysis set; n: Number of subjects included in the analysis; Geomean: Geometric mean; Max: Maximum value; Min: Minimum value; CV: Coefficient of variation (%); NA: Not applicable; NC: Not calculated* Part 2 PK on day 7 and Part 3 PK on day 10

Systemic accumulation of compound 1 after multiple administrations was evident in healthy volunteers, with geometric mean Rac AUC and Rac Cmax ranging from 3.89 to 4.69 and 1.84 to 2.83, respectively. Similar accumulation was measured in patients administered 1.4 and 3 mg of compound 1 (geometric mean: Rac AUC 4.31 and 4.23, respectively; Rac Cmax 1.56 and 2.11, respectively).

Based on geometric mean and individual trough concentrations, steady state was reached approximately 6 days after BID administration. This was consistent across dosage levels and between healthy volunteers and patients.

Within the 0.4 to 1.4 mg BID dose range, inter-subject variability was largely consistent, with no significant difference between healthy volunteers and patients. Following a single dose, the geometrical CV ranged from 56.3% to 80.7% for Cmax and from 20.1% to 37.1% for AUCτ. After multiple doses, variability was lower, with the geometrical CV ranging from 16.4% to 30.8% for Cmax and from 10.3% to 25.7% for AUCτ.

The summary of the PK data for parts 2 and 3 is shown in the table below: Analysis of visits Parameters (units) Part 2 - Health Volunteers Part 3 - Patients n Compound 1 DPI dosage: 0.4, 1.4 and 3 mg BID n Compound 1 DPI dosage: 0.4, 1.4 and 3 mg BID Slope estimate (95% CI) Slope estimate (95% CI) Day 1 of the PK Cmax (nmol/L) 18 0.9329 (0.5436, 1.322) 13 0.4324 (-0.4416, 1.306) AUCτ (h*nmol/L) 18 1.231 (1.041, 1.421) 13 0.7402 (0.3879, 1.092) PK Day 7 or Day 10* Cmax (nmol/L) 18 1.024 (0.8834, 1.164) 12 0.8684 (0.4655, 1.271) AUCτ (h*nmol/L) 18 1.136 (0.9985, 1.274) 12 0.7300 (0.4049, 1.055) MAD: Multiple Incremental Dosage; DPI: Dry Powder Inhaler; n: Number of data points used in the regression; CI: Confidence Interval. * Part 2 PK Day 7 and Part 3 PK Day 10 models: The linear model used is log(Y) = intercept + slope * log(dose), where Y is a parameter estimate; the natural logarithm has been used. Taking the sine of both sides of this equation yields the general form of the powder model: Y = exp(intercept) * (dose) ^ slope. The slope parameter is obtained using ordinary least squares.

This shows that in healthy volunteers, the increases in Cmax and AUCτ were roughly proportional to the dose within the 0.4 to 3 mg BID range. (Data from exhaled nitric oxide fractions in Phase 1, Part 3 of the clinical trial.)

Data on exhaled nitric oxide fractions from Phase 1, Part 3 of the clinical trial are shown in the table below. Table 18 (FeNO, relative changes from baseline 2 hours after morning dose (Day 1 to Day 10), linear mixed model with observational cases: Part 3 (BID MAD) (safety analysis set)): Relative change from the baseline ^a Variable (unit) Scheduled date/time treatment N n Geometric LS Mean 90% CI compare Geometric LS mean ratio 90% CI difference p-value FeNO (ppth) Until the 10th day A collection of placebos 4 4 0.979 (0.478, 2.006) Compound 1, 1.4 mg DPI 6 6 0.461 (0.228, 0.931) Compound 1, 1.4 mg DPI versus the collected placebo 0.471 (0.334, 0.663) 0.002 Compound 1, 3 mg DPI 7 7 0.465 (0.231, 0.938) Compound 1, 3 mg DPI versus the collected placebo 0.475 (0.335, 0.674) 0.002 The baseline for ^the FeNO analysis will be the mean FeNO measurements corresponding to Day 1 and Day 2 of the endpoint being analyzed. Results are based on the MMRM, using FeNO assessments 2 hours after all baseline doses. Log-transformed FeNO data are analyzed to normalize the skewed distribution of this endpoint, with the relative change from the baseline logarithmic transformation as the primary dependent variable, treatment, visit, and visit-to-treatment interactions as fixed effects, and the random effect of subjects and the log-transformed baseline FeNO as covariates. BID, twice daily; CI, confidence interval; DPI, dry powder inhaler; LS, least squares; MAD, multiple escalation dose; MMRM, mixed-effects model of repeated measurements; n, number of data points included in the analysis; N, number of subjects in the safety analysis set. Table 19 (FeNO, relative changes in morning predose (days 1 to 10) from baseline, with a linear mixed model of observed cases: Part 3 (BID MAD (safety analysis set): Relative change from the baseline ^a Variable (unit) Scheduled date/time treatment N n Geometric LS Mean 90% CI compare Geometric LS mean ratio 90% CI difference p-value FeNO (ppth) Until the 10th day A collection of placebos 4 4 0.927 (0.504, 1.704) Compound 1, 1.4 mg DPI 6 6 0.453 (0.250, 0.822) Compound 1, 1.4 mg DPI versus the collected placebo 0.489 (0.360, 0.665) 0.001 Compound 1, 3 mg DPI 7 7 0.391 (0.216, 0.708) Compound 1, 3 mg DPI versus the collected placebo 0.422 (0.308, 0.577) <0.001 The baseline for ^the FeNO analysis will be the mean FeNO measurements corresponding to Day 1 and Day 2 of the endpoint being analyzed. Results are based on the MMRM, using FeNO assessments 2 hours after all baseline doses. Log-transformed FeNO data are analyzed to normalize the skewed distribution of this endpoint, with the relative change from the baseline logarithmic transformation as the primary dependent variable, treatment, visit, and visit-to-treatment interactions as fixed effects, and the random effect of subjects and the log-transformed baseline FeNO as covariates. BID, twice daily; CI, confidence interval; DPI, dry powder inhaler; LS, least squares; MAD, multiple escalation dose; MMRM, mixed-effects model of repeated measurements; n, number of data points included in the analysis; N, number of subjects in the safety analysis set. Table 20 ((FeNO, evening dose (days 1 to 9) relative changes from baseline, with observational cases in a linear mixture model: Part 3 (BID MAD (safety analysis set):) Relative change from the baseline ^a Variable (unit) scheduled date/time treatment N n Geometric LS Mean 90% CI compare Geometric LS mean ratio 90% CI difference p-value FeNO (ppth) Until the 10th day A collection of placebos 4 4 0.914 (0.708, 1.179) Compound 1, 1.4 mg DPI 6 6 0.419 (0.338, 0.518) Compound 1, 1.4 mg DPI versus the collected placebo 0.458 (0.331, 0.635) <0.001 Compound 1, 3 mg DPI 7 7 0.360 (0.295, 0.441) Compound 1, 3 mg DPI versus the collected placebo 0.394 (0.283, 0.549) <0.001 [ ^a ] The baseline for the FeNO analysis will be the mean FeNO measurements corresponding to Day 1 and Day 2 of the endpoint being analyzed. Results are based on MMRM, using FeNO assessments 2 hours after all baseline doses. Log-transformed FeNO data are analyzed to normalize the skewed distribution of this endpoint, with the relative change from the baseline logarithmic transformation as the primary dependent variable, the interaction of treatment, visits, and follow-up treatment as fixed effects, and the random effects of subjects and the log-transformed baseline FeNO as covariates. BID, twice daily; CI, confidence interval; DPI, dry powder inhaler; LS, least squares; MAD, multiple escalation dose; MMRM, mixed-effects model of repeated measurements; n, number of data points included in the analysis; N, number of subjects in the safety analysis set.

Figure 7 shows the relative change of FeNO from baseline within 2 hours after the morning dose (based on MMRM analysis plots at time points, Part 3, Safety Analysis Set). In Figure 7: Dosage placebo 1.4 mg 4 mg symbols ○ ó r

This indicates that, compared with placebo, both 1.4 mg and 3 mg of compound 1 showed significant changes from baseline in FeNO levels 2 hours after the morning dose from day 1 to day 10 (p = 0.002). Similarly, compared with placebo, the changes from baseline in FeNO levels at the morning pre-dose (days 1 to 9 and day 10) and evening pre-dose from day 1 to day 9 were highly significant (p ≤ 0.001).

This data demonstrates that, with twice-daily doses of 1.4 mg and 3.0 mg, the lung inflammatory biomarker FeNO was reduced by approximately 50% in participants with mild asthma compared to placebo. This data also demonstrates a good effect before and after medication, proving that the twice-daily regimen provides 24-hour coverage. Example 3 - Phase 2a Clinical Trial

Phase 2a of the clinical trial is to be completed. Overall design summary:

This is a phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study designed to evaluate the efficacy, safety, and pharmacokinetic (PK) of compound 1 administered by BID at a single dose level using an SD3FL dry powder inhaler over a 12-week treatment period in adult participants with uncontrolled moderate to severe asthma. The study will include approximately 150 research sites worldwide.

Approximately 320 participants, who, despite receiving moderate or high doses of ICS-LABA at screening and at visit 3, had uncontrolled asthma (Asthma Control Questionnaire-6 score ≥ 1.5), were randomly assigned in a 1:1 ratio to one of two treatment groups (Compound 1 1.4 mg BID or placebo). To ensure balance between treatment groups, randomization was stratified based on participants' ICS dose levels (moderate or high) and region at visit 1. Compound 1, 1.4 mg, and placebo were administered BID using an SD3FL inhaler, known and marketed in Europe as ^GENUAIR® and in the United States as ^PRESSAIR® .

Approximately 320 participants, who, despite receiving intermediate or high doses of ICS-LABA (inhaled corticosteroid long-acting beta-receptor agonist) at screening and at visit 3, had uncontrolled asthma (ACQ-6 score ≥ 1.5), were randomly assigned in a 1:1 ratio to one of two treatment groups (compound 1, 1.4 mg BID or placebo). This could be adjusted to approximately 385 participants after the planned intraoperative isolation (IA). To ensure balance between treatment groups, randomization was stratified based on participants' ICS dose level (intermediate or high) and region at visit 1. In addition, at least 40% of participants will have a FeNO value of ≥ 25 ppb at Visit 3, and at least 30% of participants randomly selected in the study will have a recorded history of ≥ 2 severe asthma exacerbations within 1 year prior to Visit 1. Core Inclusion Criteria : 1. Participants must be 18 to 80 years of age (inclusive) at the time of signing the informed consent form. 2. Participants must have been treated with a combination of intermediate-to-high dose ICS and a stable dose LABA for at least 3 months prior to Visit 1 (ICS may be included in the ICS-LABA fixed-dose combination product). - Participants are permitted to have been treated with a stable dose of additional asthma control therapy (e.g., LAMA, LTRA) for ≥ 3 months prior to Visit 1. Treatment with maintenance systemic corticosteroids (oral or injectable) is not permitted. 3. A history of at least one severe asthma exacerbation within the year prior to visit 1. A severe asthma exacerbation is defined as an asthma worsening that results in any of the following: - Treatment with systemic corticosteroids for at least 3 consecutive days to treat asthma worsening symptoms (a single deposition dose of injectable corticosteroids will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids). - An emergency room visit requiring systemic corticosteroids (as described above) for asthma (defined as assessment and treatment in the emergency department lasting < 24 hours). - Hospitalization due to asthma (defined as admission to an inpatient facility and/or ≥ 24 hours of assessment and treatment in a healthcare facility). In this protocol, an acceptable record of severe asthma exacerbation is: - A recorded systemic corticosteroid prescription for at least 3 days to treat the asthma worsening (a single deposition dose of injectable corticosteroid will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids). For participants with an established self-management plan, recorded prescription filling will be considered adequate. - Clinical visit or consultation (primary or specialist HCP) records providing evidence of at least one exacerbation within the 12 months prior to enrollment. - Record participants' participation in emergency room visits due to the need for systemic corticosteroids for asthma (as described above) (defined as assessment and treatment in the emergency department for <24 hours). - Instruct participants on discharge summaries from hospitals, emergency rooms, or intensive care units where they were hospitalized for asthma (defined as assessment and treatment in an inpatient facility and/or healthcare facility for ≥24 hours). 4. Predicted morning pre-BD FEV1 between ≥40% and ≤90% at visits 1 and 3 (before randomization). 5. Able to perform acceptable FEV1 pulmonary function tests according to the ATS/ERS 2019 acceptability criteria. 6. Within 10 years up to or including visit 1, there is documented evidence of asthma as demonstrated by any of the following: - Reversibility of FEV1 after BD ≥ 12% and ≥ 200 mL, or - Mean daily variability of PEF > 10% over a 2-week period, or - Variation of FEV1 > 12% and 200 mL between any two clinical visits, or - A positive bronchial challenge test (a positive test is defined as a decrease in FEV1 ≥ 20% from before the challenge with a standard dose of acetylcholine or histamine, or a decrease in FEV1 ≥ 15% from before the challenge with standardized hyperventilation, hypertonic saline, or mannitol), or - A positive exercise challenge test (a positive test is defined as a decrease in FEV1 > 10% and > 200 mL from the point of attack), or - a FeNO test value ≥ 40 ppb despite confirmed ICS maintenance therapy. If no documentation supports either of these diagnostic criteria, and if the investigator considers a clinical diagnosis of asthma still plausible, then investigating and confirming a mean daily variability of PEF > 10% over a 2-week period is also considered sufficient to confirm a diagnosis of asthma during the screening and adjustment period. 7. ACQ-6 score ≥ 1.5 at Visits 1 and 3 (before randomization). 8. Able and willing to comply with CSP requirements, including the ability to read, write, and fluently use the translation languages of all participants in the questionnaires used at the research site, and to use electronic devices such as ePRO devices and spirometers. 9. Weight ≥ 40 kg and BMI < 35 kg/ ^m² . 10. Male and/or female.

Women using birth control pills must comply with local regulations regarding the contraceptive methods used by those participating in clinical trials. There are no restrictions on male participants or their female partners.

Women deemed infertile are defined as permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or postmenopausal. The following age-specific requirements apply: - Women < 50 years of age who have been menopausal for 12 months or longer after discontinuing exogenous hormone therapy and whose follicle-stimulating hormone (FSH) levels are within the postmenopausal range are considered postmenopausal. - Women ≥ 50 years of age who have been menopausal for 12 months or longer after discontinuing all exogenous hormone therapy are considered postmenopausal. - All FOCBPs who have sexual relations with unsterilized male partners must agree to use one of the following highly effective methods of contraception for at least 3 months prior to visit 1 and throughout the study, and 1 month after the last dose of IMP. Discontinuing contraception after this should be discussed with your attending physician. A highly effective method of contraception is defined as having a failure rate of <1% per year when used consistently and correctly. - The following contraceptive methods are unacceptable: periodic abstinence (calendar method, symptom temperature method, post-ovulation method), abstinence during the duration of IMP exposure, withdrawal (intercourse interruption), spermicide-only use, and amenorrhea during breastfeeding. Female and male condoms should not be used together. - All FOCBPs must have a negative serum pregnancy test result at visit 1. - Effective contraceptive methods include: complete abstinence as an acceptable method, provided it is the participant's usual lifestyle (defined as avoiding heterosexual intercourse throughout the entire risk period associated with IMP), partner vasectomy, IMPLANON, bilateral tubal occlusion, intrauterine devices/levonorgestrel intrauterine contraceptive systems, DEPO-PROVERA injections, oral contraceptives, and EVRA PATCH, XULANE, or NUVARING. 11. Ability to obtain informed consent prior to any study-specific procedure. 12. Providing signed and dated written informed consent for the genetic research information selected on an ad hoc basis before collecting samples for genetic research supporting the Genomics Initiative. Randomization Inclusion Criteria

At the end of the adjustment period (Visit 3), participants must meet the following additional criteria to be randomized into the study and enter the treatment phase: 1. Pre-BD FEV1 is ≥ 40% to ≤ 90% of the predicted value (before randomization). 2. Pre-BD/IMP dose-pre-BD FEV1 at Visit 3 is not 20% or more greater than the pre-BD FEV1 recorded at Visits 1 and 2. 3. ACQ-6 score ≥ 1.5 (before randomization). 4. At least 80% adherence to routine asthma medication during the adjustment period (from Visit 2 to Visit 3) based on daily asthma ePRO. 5. At least 80% adherence as assessed by daily eCOA. Compliance was defined as completing the daily ePRO questions and PEF measurements (morning and evening) for at least 80% of the time during the adjustment period and the 14 days prior to visit 3. For female participants, a negative urine pregnancy test prior to IMP administration was required (randomized). Core exclusion criteria: 1. Severe asthma exacerbation within 8 weeks prior to randomization. 2. History of shingles reactivation, such as herpes zoster. 3. Participants with severe COVID-19 illness within 6 months of enrollment: - Participants diagnosed with COVID-19 pneumonia based on radiological evaluation. - Participants diagnosed with COVID-19 requiring hospitalization and/or oxygen therapy. 4. Clinically important lung diseases other than asthma, such as active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-related hypoventilation syndrome, lung cancer, previous or planned lobectomy, alpha-1 antitrypsin deficiency, primary ciliary dyskinesia, Churg-Strauss syndrome, allergic bronchopulmonary erythrombosis, and eosinophilia syndrome. 5. Any condition that the investigator considers unstable, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematologic, psychiatric, or major physical injury, and which may: - affect the safety of participants throughout the study, - affect the findings of the study or its interpretation, or - impair the participant's ability to complete the duration of the study. 6. Any clinically significant cardiovascular or cerebrovascular disease: - within 6 months of visit 1, unstable angina, acute coronary syndrome (acute myocardial infarction, unstable angina), percutaneous coronary intervention/coronary artery bypass grafting, or stroke. - Heart failure, New York Heart Association class II to IV. - Systemic hypertension unless well controlled and stable for at least 6 months with two or fewer medications. - Untreated high-degree atrioventricular block (second- or third-degree atrioventricular block)/significant sinus node dysfunction/pause or need for treatment of tachycardia. Participants may include those with atrial fibrillation or flare and an optimal controlled ventricular rate of <100 bpm at rest, as determined by the investigator. - A history or family history of long QT syndrome or sudden cardiac death in individuals <40 years of age. - A history of QT prolongation associated with other medications requiring discontinuation of this medication. - Hypertrophic cardiomyopathy or clinically significant valvular heart disease. Idiopathic pulmonary hypertension or pulmonary hypertension caused by connective tissue or thromboembolic disease. 7. History of venous thromboembolism. 8. Participants with evidence of active TB (treated or untreated) or latent TB as determined by the investigator but who have not completed appropriate treatment or are receiving appropriate preventative care. Assessment will be conducted according to local nursing standards as defined by local guidelines and may consist of medical history and physical examination, chest X-ray, or TB testing (e.g., purified protein derivatives or ^{QuantiFERON®} test). 9. Participants with a recent history of infectious hepatitis or unexplained jaundice, or who tested positive for hepatitis, hepatitis B, hepatitis C, or HIV. Participants will be excluded from the study if they meet any of the following criteria: - Participants with positive hepatitis C antibodies. - Participants with positive hepatitis B surface antigen. - Participants with positive hepatitis B core antibodies. - Participants with a history of HIV infection or who tested positive for HIV. Note: Participants with a history of hepatitis B vaccination but no history of hepatitis B are permitted. If a vaccinated participant tests positive for hepatitis B antibodies, a confirmatory PCR test will be performed. 10. Current or previous history of alcohol or drug abuse (including cannabis), as determined by the investigator. If the investigator determines that a positive drug screening result cannot be supported by the participant's medical history and related treatments (non-prescription products or effective prescriptions), or current history of alcohol or drug abuse (including cannabis and effective prescriptions containing cannabis). 11. History of malignant tumors other than superficial basal cell carcinoma. Previous/concomitant therapy 12. Use of systemic corticosteroids (short-term or maintenance) for 4 weeks (oral) or 8 weeks (intramuscular) prior to Visit 1. 13. Any immunosuppressive therapy (including hydroxychloroquine, methotrexate, cyclosporine, and tacrolimus) within 12 weeks prior to Visit 1. 14. Treatment with commercially available biologics (including benralizumab, mepolizumab, reslizumab, omalizumab, dupilumab, and tezepelumab) for 6 months, whichever is longer than 1 or 5 half-lives, is permitted. 15. Inhaled corticosteroid β2 agonists (e.g., Symbicort, Fostair, or Airsupra) are not permitted as rehydration agents for 15 days prior to Visit 1, during the screening/adjustment period, throughout the entire treatment period, and preferably 1 week after the last dose of IMP. 16. Received a live, attenuated, or mRNA vaccine within 4 weeks of Visit 1. 17. Received immunoglobulin or blood products within 4 weeks of Visit 1. 18. Received any immunotherapy within 6 months of Visit 1, except for stable maintenance allergen-specific immunotherapy that started at least 4 weeks prior to Visit 1 and is expected to continue until the end of the follow-up period. Previous/Concurrent Clinical Study Experience 19. Enrolled in another clinical study concurrently. 20. Participants treated with any investigational drug within 4 months (or 5 half-lives, whichever is longer) prior to Visit 1. 21. Participants with a known hypersensitivity reaction to any excipient of Compound 1 or the product. Diagnostic Assessment 22 Abnormal findings identified on physical examination, ECG, or laboratory tests include, but are not limited to: - ALT or AST ≥ 1.5 × ULN. - TBL ≥ ULN (unless due to known Gilbert's disease). - Evidence of chronic liver disease. - Abnormal vital signs after 5 minutes of supine or sitting rest (confirmed by a single control measurement), defined as any of the following: ○ Systolic BP < 80 mmHg or ≥ 150 mmHg. ○ Diastolic BP < 50 mmHg or ≥ 95 mmHg. ○ Pulse < 50 bpm or > 100 bpm. - Signs of pulmonary edema or volume overload. - Any clinically significant rhythm, conduction, or morphological abnormality in the ECG, including but not limited to QTcF > 450 ms. Additionally, any other clinically relevant abnormality found in physical examinations or laboratory tests (including hematology, coagulation, serology, urinalysis, or ECG) between Visit 1 and Visit 3 (randomized) that the investigator or medical monitor believes may impair the safety of the study participants or interfere with the assessment of IMP. Other exclusions: 23. Applicable only to female participants – currently pregnant (confirmed by a positive pregnancy test) or breastfeeding. 24. Current smokers or participants with a smoking history of ≥ 10 pack-years. - Note: Pack-years are calculated as average number of cigarettes smoked per day × number of years / 20. For example, 1 pack-year = smoking 20 cigarettes a day for 1 year or 10 cigarettes a day for 2 years. - Smokers or e-cigarette users with a smoking history of < 10 pack-years must have quit smoking for at least 6 months prior to visit 1. 25. Participants with known long-term exposure to occupational asbestos, silicon dioxide, radon, heavy metals, and polycyclic aromatic hydrocarbons. 26. Positive family history of lung cancer (the decision to include participants with a positive family history of lung cancer will be made by the investigator in consultation with medical monitors based on the specific circumstances). 27. A positive urine cotinine test or an exhaled carbon monoxide test at Visit 1 and at any point during the study. 28. Participation in the study program and/or its implementation (applicable to AstraZeneca employees and/or on-site staff). 29. If a participant is unlikely to comply with the study procedures, limitations, and requirements, the investigator determines that the participant should not participate in the study. 30. Donating blood (≥ 450 mL) within 3 months prior to Visit 1 or donating plasma within 14 days prior to Visit 1. 31. Undergoing major surgery within 8 weeks prior to Visit 1, or undergoing planned inpatient surgery, major dental procedures, or hospitalization during screening, treatment, or follow-up. Dosage

The test doses are 1.4 mg twice daily, 0.9 mg twice daily, and 0.4 mg twice daily. Therefore, the daily doses for testing are 0.8 mg, 1.8 mg, or 2.8 mg.

The proposed dosage regimen of 1.4 mg BID (2.8 mg/day) is based on safety and efficacy biomarker data observed in a Phase 1 study (D8210C00001). In the Phase 1 study (D8210C00001), the 1.4 mg BID dosage was found to be safe and well-tolerated, and resulted in a reduction of approximately 50% in the pulmonary inflammatory biomarker FeNO in participants with mild asthma compared to placebo. This level of FeNO reduction is considered a good indicator of potential clinical efficacy.

The term dosage refers to the device delivery dosage of compound 1. The dosage selection is based on target binding (FeNO level) and safety data from the Phase 1 study (D8210C00001).

Therefore, a 1.4 mg BID dose is considered to provide the best risk/benefit profile for evaluation in further clinical development based on available data. Table 21 - Phase 2 primary objectives, endpoints, and estimates. Main objectives Terminal and estimated value To evaluate the clinical efficacy of compound 1 1.4 mg BID compared to placebo in adult participants with moderate to severe uncontrolled asthma. Population : The analysis will include participants randomized to either placebo or Compound 1 (1.4 mg BID group). Endpoint : Time to the first CompEx (aggravated combined endpoint) event. Population-level aggregate measures : Risk ratio and survival estimates using the Kaplan-Meier estimator. Intermittent event strategy : Primary estimate : At treatment – if an intermittent event occurs before the first CompEx event, participants will be screened at the time of the intermittent event. Supporting estimate: Treatment policy (reflecting the ITT – intention-to-treat principle) – after the intermittent event, participants remain in the study to allow for the study endpoint up to week 12. Treatment policy strategy used to estimate the efficacy of Compound 1 under “real-world” conditions. Table 22 - Secondary objectives, endpoints and estimates for Phase 2. Secondary objectives Terminal and estimated value To evaluate the clinical efficacy of compound 1 1.4 mg BID compared to placebo in adult participants with moderate to severe uncontrolled asthma. Population : The analysis will include participants randomized to either placebo or compound 1 (1.4 mg BID group). Endpoints**: Changes from baseline: 1. Pre-BD FEV1 (forced expiratory volume in one second) at weeks 4 and 12; 2. CAAT (Chronic Airway Assessment Test) at weeks 4 and 12; 3. ACQ-6 (Asthma Control Questionnaire-6) at weeks 4 and 12; 4. Mean morning and evening PEF (peak expiratory flow) at weeks 4 and 12, and the mean over the 12-week treatment period; 5. Daily asthma symptom scores (total, daytime, and nighttime) at weeks 4 and 12. Population level aggregate measure : Mean change from baseline. Intermittent event strategy : Same as the primary objective. Population : The analysis will include participants randomly assigned to either placebo or compound 1 (1.4 mg BID group). Endpoints: 1. Time to first CompEx (aggravated composite endpoint) acute exacerbation event 2. CompEx (aggravated composite endpoint) event rate 3. CompEx (aggravated composite endpoint) acute exacerbation event rate Population-level aggregate measures : 1. Risk ratio and survival estimate using the Kaplan-Meier estimator 2. (a) Percentage of participants with at least one event (b) Event rate normalized over the study follow-up duration (12 weeks) 3. (a) Percentage of participants with at least one event (b) Event rate normalized over the study follow-up duration (12 weeks) Intermittent event strategies : 1. During treatment 2. Treatment policy 3. Treatment policy To evaluate the effect of compound 1, as measured by FeNO, on airway inflammation. Population: The analysis will include participants randomly assigned to either placebo or compound 1 (1.4 mg BID group). Endpoint**: Change in FeNO from baseline at weeks 4 and 12. Population-level aggregate measure : Mean change from baseline to weeks 4 and 12. Interstitial event strategy : Same as the primary objective. To evaluate the effect of compound 1 1.4 mg BID on cough in adult participants with moderate to severe uncontrolled asthma compared to placebo. Population : The analysis will include participants randomly assigned to either placebo or compound 1 (1.4 mg BID group). Endpoint** : Change in cough severity from baseline at weeks 4, 12, and throughout the treatment period. Population-level aggregate measure : Mean change from baseline. Intermittent event strategy : Same as the primary objective. To evaluate the pharmacokinetic (PK) of compound 1 in all participants after 4 and 12 weeks of drug administration. Population : All participants who have received at least one dose of Compound 1 and have at least one measurable PK sample after the first dose. Endpoint**: Plasma concentration of Compound 1 before and after the week 4 dose, and before the week 12 dose. Population-level pooled measures : Pooled statistical measures of intervening events. Strategy : During treatment. ** The time points included in the estimates are: Baseline = V3 (Day 1); Week 4 = V5 (29 days ± 3 days); Week 12 = V7 (85 days ± 3 days).

Interim events are events that occur after treatment initiation (e.g., IMP discontinuation, terminal events such as death), and their impact is measured or interpreted in aggregate measures (e.g., risk ratio) related to the clinical issues of concern. Table 23 - Phase 2 safety objectives, endpoints, and estimates. Secondary objectives Terminal and estimated value To evaluate the safety and tolerability of compound 1 1.4 mg BID in adult participants with moderate to severe uncontrolled asthma. Population : The analysis will include all participants randomized to either placebo or compound 1 (1.4 mg BID group). Endpoint : Safety and tolerability assessments using all adverse events, vital sign measures, clinical laboratory evaluations, and ECG (electrocardiogram). Population-level pooled measures : Descriptive statistics including absolute counts and frequency. Intermittent event strategy : Primary estimate: At treatment – If an intermittent event occurs, no subsequent safety data will be considered in the safety assessment after the safety follow-up. Supporting estimate: Treatment policy – If an intermittent event occurs, the participant remains in the study, and any safety data up to the week 12 safety follow-up will be considered in the safety assessment. Table 24 Pharmacokinetic Parameters Parameters explain Cmax Maximum observed plasma concentration tmax Time to reach maximum observable concentration after drug administration λz Terminal elimination rate constant, a linear regression estimate of the terminal portion of the logarithmic concentration versus time curve. t½λz Half-life associated with the terminal slope (λz) of the semi-log concentration-time curve AUC(0-12) Area under the plasma concentration-time curve from time 0 to 12 hours AUC(0-24) Area under the plasma concentration-time curve from time 0 to 24 hours AUClast Area under the plasma concentration curve from zero to the last quantifiable concentration. AUCinf Area of plasma concentration from zero to infinity under the time curve CL/F Apparent systemic clearance of drug after extravascular administration and post-administration via plasma (inhalation and oral groups only) CL Systemic clearance of drug from plasma after intravenous administration (Group IV only) Vz/F Distribution volume (apparent) at extravasation and post-steady-state (based on end-stage) (inhalation and PO group only) Vz Distribution volume after intravascular injection (based on end-stage) (Group IV only) AUClast/D The dose normalization AUClast is obtained by dividing the AUClast by the dose administered. AUCinf/D The dose normalization AUCinf is obtained by dividing AUCinf by the dose administered. Cmax/D The dosage normalization Cmax is obtained by dividing Cmax by the administered dosage. tlast The time it took to finally observe (quantifiable) concentration AUCτ Plasma concentration-time curve at dose intervals Rac AUC Cumulative ratio of AUCτ (reported for day 7 [part 2] or day 10 [part 3]) Rac Cmax Cmax cumulative ratio (for Day 7 [Part 2] or Day 10 [Part 3] report) tlast The time it took to finally observe (quantifiable) concentration λz is relatively low The lower (earlier) t used to determine λz λz is higher Used for determining the higher (later) t of λz. λzN The number of data points determined by λz λz span ratio The time interval for determining λz as the ratio of t½λz Rsq The approximate statistical measure used for regressions determined by λz. Rsq adj The approximate statistic used for regressions determined by λz is adjusted according to the number of data points used. AUCextr The area extrapolated from tlast to the infinite curve is expressed as a percentage of AUCinf. Ae(t1-t2) The cumulative amount of unchanged drug excreted into urine from time t1 to time t2. fe(t1-t2) The cumulative percentage of the dose excreted in urine from time t1 to time t2 without changing the amount excreted. CLR Drug clearance from plasma References

Several publications have been cited above. Full citations of these references are provided below. The full text of each of these references is incorporated herein by reference. References Doi Pithani 2023 Subhash Pithani, Carl-Johan Aurell, Marika Lindhagen, Michael Nunn, Kristina Berggren, and Hans Emtenäs, Org. Process Res. Dev. 2023, 27, 1317−1329 10.1021/acs.oprd.3c00077 Schindler C 1995 Schindler C, and Darnell JE Jr., Annu. Rev. Biochem. 1995; 64;621-651 10.1146/annurev.bi.64.070195.003201 O'Shea 2013 John J O'Shea, Steven M Holland, Louis M Staudt, N Engl J Med, 2013, 368, 161-170 10.1056/NEJMra1202117 Leonard 2000 WJ Leonard, JX Lin, J. Allergy Clin. Immunol, 2000, 105: 877-888 10.1067/mai.2000.106899 Frank 1999 Frank, Mol. Med. 1999, 5:432-456 10.1007/bf03403538 Vijayakriishnan 2011 L Vijayakriishnan, R Venkataramanan, Palak Gulati, Trends Pharmacol. Sci, 2011, 32, 25-34 10.1016/j.tips.2010.10.004 Laurence 2012 Arian Laurence, Marko Pesu, Olli Silvennoinen, John O'Shea, Open Rheumatol J. 2012, 6, 232-244; 10.2174/1874312901206010232 Clark 2014 James D. Clark, Mark E. Flanagan, and Jean-Baptiste Telliez, J. Med. Chem. 2014, 57, 5023-5038. 10.1021/jm401490p Ashino 2014 Shigeru Ashino, Katsuyuki Takeda, Hui Li, Vanessa Taylor, Anthony Joetham, Polly R Pine, Erwin W Gelfand, J Allergy Clin Immunol, 2014; 133, 1162-74, 10.1016/j.jaci.2013.10.036 Herrera 2015 Norma Elizabeth Vázquez-Herrera & Antonella Tosti, Expert Opinion Orphan Drug, 2015, 3 (4), 419-431. 10.1517/21678707.2015.1021778 Ghoreschi 2014 Kamran Ghoreschi, Massimo Gadina, Exp. Dermatol. 2014, 23 (1), 7-11. 10.1111/exd.12265 Pesu 2008 Marko Pesu, Arian Laurence, Nandini Kishore, Samuel H Zwillich, Gary Chan, John J O'Shea, Immunol. Rev. 2008, 223, 132-142. 10.1111/j.1600-065X.2008.00644.x Haan 2011 Claude Haan, Catherine Rolvering, Friedrich Raulf, Manuela Kapp, Peter Drückes, Gebhard Thoma, Iris Behrmann, Hans-Günter Zerwes, Chem. Biol. 2011, 18 (3), 314-323 10.1016/j.chembiol.2011.01.012 Van Vollenhoven 2019 Van Vollenhoven R, Lee EB, Strengholt S, Mojcik C, Valdez H, Krishnaswami S, et al. Arthritis Rheumatol. 2019; 71(5): 685–95. 10.1002/art.40780 Barnes 2018 Barnes PJ, Nature Reviews Immunol, 2018, 18, 454–66. 10.1038/s41577-018-0006-6 Barnes 2014 Barnes PJ, Chem Immunol Allergy, 2014, 100, 311-6. 10.1159/000359984 GINA 2022 Global initiative for asthma. Global strategy for asthma management and prevention. 2022. Available from URL: https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf. For standard molecular biology techniques, see Sambrook, J., Russell, DW Molecular Cloning, A Laboratory Manual. 3rd ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press. Statement: 1. A method for treating or preventing diseases or disorders in which JAK1 inhibition is beneficial, comprising administering a compound of formula (I) to an individual in need at a daily dose of 0.8 mg to 6.2 mg of free base: (I) or a medically acceptable salt thereof. 2. The method of claim 1, wherein the beneficial disease or condition of JAK1 inhibition is selected from type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis arthritis, juvenile idiopathic arthritis, axial spondylitis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), vitiligo, and alopecia areata. 3. The method of claim 2, wherein the beneficial disease or condition of JAK1 inhibition is asthma. 4. The method of claim 2, wherein the beneficial disease or condition of JAK1 inhibition is COPD. 5. The method as stated in any of claims 1 to 4, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of at least 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, or 1.0 mg daily. Administer daily doses of free base at doses of 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, or 5.5 mg. 6. The method as stated in any of claims 1 to 4, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in doses of up to 6.2 mg, 6.1 mg, 6.0 mg, 5.9 mg, 5.8 mg, 5.7 mg, 5.6 mg, 5.5 mg, 5.4 mg, 5.3 mg, 5.2 mg, 5.1 mg, 5.0 mg, 4.9 mg, 4.8 mg, 4.7 mg, 4.6 mg, 4.5 mg, 4.4 mg, 4.3 mg, 4.2 mg, 4.1 mg, 4.0 mg, 3.9 mg, 3.8 mg, 3.7 mg, 3.6 mg, 3.5 mg, 3.4 mg, 3.3 mg, 3.2 mg, 3.1 mg, 3.0 mg, 2.9 mg, 2.8 mg, 2.7 mg, 2.6 mg, 2.5 mg, 2.4 mg, 2.3 mg, 2.2 mg, 2.1 mg, or 2.1 mg per day. 7. Administered at a daily dose of 2.8 mg of free base, in the form of a pharmaceutically acceptable salt, of any of the following methods: 1. 2.0 mg, 1.9 mg, 1.8 mg, 1.7 mg, 1.6 mg, 1.5 mg, 1.4 mg, 1.3 mg, 1.2 mg, 1.1 mg, or 1.0 mg. 8. Administered at a daily dose of 1.8 mg of free base, in the form of a pharmaceutically acceptable salt, of any of the following methods: 1. 2.0 mg, 1.9 mg, 1.8 mg, 1.8 mg, 1.7 mg, 1.6 mg, 1.5 mg, 1.4 mg, 1.3 mg, 1.2 mg, 1.1 mg, or 1.0 mg. 9. The method of any of claims 1 to 6, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at a daily dose of 0.8 mg of free base. 10. The method of any of claims 1 to 6, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at a daily dose of 6.0 mg of free base. 11. The method of any of claims 1 to 10, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at a daily dose of 0.4 to 3.1 mg of free base twice daily. 12. The method as described in any of claims 1 to 11, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at doses of at least 0.4 mg twice daily, 0.45 mg twice daily, 0.5 mg twice daily, 0.6 mg twice daily, 0.65 mg twice daily, 0.7 mg twice daily, 0.75 mg twice daily, 0.8 mg twice daily, 0.85 mg twice daily, 0.9 mg twice daily, 0.95 mg twice daily, 1.0 mg twice daily, 1.05 mg twice daily, 1.1 mg twice daily, 1.15 mg twice daily, 1.2 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, 1.6 ...6 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.5 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.6 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.6 mg twice daily, 1.6 mg twice Dosage of free bases at doses of 1.65 mg twice daily, 1.7 mg twice daily, 1.75 mg twice daily, 1.8 mg twice daily, 1.85 mg twice daily, 1.9 mg twice daily, 2.0 mg twice daily, 2.05 mg twice daily, 2.1 mg twice daily, 2.15 mg twice daily, 2.2 mg twice daily, 2.25 mg twice daily, 2.3 mg twice daily, 2.35 mg twice daily, 2.4 mg twice daily, 2.45 mg twice daily, 2.5 mg twice daily, 2.55 mg twice daily, 2.6 mg twice daily, 2.7 mg twice daily, or 2.75 mg twice daily. 13. The method of any one of claims 1 to 11, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered in doses of up to 3.1 mg twice daily, 3.05 mg twice daily, 3.0 mg twice daily, 2.95 mg twice daily, 2.9 mg twice daily, 2.85 mg twice daily, 2.8 mg twice daily, 2.75 mg twice daily, 2.7 mg twice daily, 2.65 mg twice daily, 2.6 mg twice daily, 2.55 mg twice daily, 2.5 mg twice daily, 2.45 mg twice daily, 2.4 mg twice daily, 2.35 mg twice daily, 2.3 mg twice daily, 2.25 mg twice daily, 2.2 mg twice daily, 2.15 mg twice daily, 2.1 mg twice daily, 2.05 mg twice daily, 2.0 mg twice daily, 1.95 ... 1.9 mg twice daily, 1.85 mg twice daily, 1.8 mg twice daily, 1.75 mg twice daily, 1.7 mg twice daily, 1.65 mg twice daily, 1.6 mg twice daily, 1.55 mg twice daily, 1.5 mg twice daily, 1.45 mg twice daily, 1.4 mg twice daily, 1.35 mg twice daily, 1.3 mg twice daily, 1.25 mg twice daily, 1.2 mg twice daily, 1.15 mg twice daily, 1.1 mg twice daily, 1.05 mg twice daily, 1.0 mg twice daily, 0.95 mg twice daily, 0.9 mg twice daily, 0.85 mg twice daily, 0.8 mg twice daily, 0.75 mg twice daily, 0.7 mg twice daily, 0.65 mg twice daily, 0.6 mg twice daily, 0.55 mg twice daily, or 0.5 mg twice daily. 14. The method of any of claims 1 to 13, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at a free base delivery dose of 1.4 mg twice daily. 15. The method of any of claims 1 to 13, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at a free base delivery dose of 0.9 mg twice daily. 16. The method of any of claims 1 to 11, wherein the compound of formula (I) in the form of a pharmaceutically acceptable salt, as appropriate, is administered at a free base delivery dose of 0.4 mg twice daily. 17. The method of any of claims 1 to 11, wherein the compound of formula (I), as appropriate, is administered as a pharmaceutically acceptable salt in a dose of 3.0 mg of free base twice daily. 18. The method of any of claims 1 to 17, wherein the compound of formula (I) is administered as a pharmaceutically acceptable salt. 19. The method of claim 18, wherein the compound of formula (I) is administered as a sinephrine. 20. The method of any of claims 1 to 4 or 19, wherein the compound of formula (I) is administered as a sinephrine in a daily dose ranging from 1.05 mg to 8.14 mg. 21. The method of claim 20, wherein the sennarate of compound (I) is administered at a dose of 1.84 mg sennarate twice daily. 22. The method of claim 20, wherein the sennarate of compound (I) is administered at a dose of 1.18 mg sennarate twice daily. 23. The method of claim 20, wherein the sennarate of compound (I) is administered at a dose of 0.53 mg sennarate twice daily. 24. The method of claim 20, wherein the sennarate of compound (I) is administered at a dose of 3.94 mg sennarate twice daily. 25. The method of any of claims 11 to 19 or 21 to 24, wherein the dose interval is 10 to 14 hours. 26. The method of claim 25, wherein the dose interval is 11 hours and 30 minutes to 12 hours and 30 minutes. 27. The method of any of claims 1 to 26, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered orally. 28. The method of any of claims 1 to 26, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in the form of an inhaled aerosol. 29. The method of any of claims 1 to 26, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered via a dry powder inhaler. 30. The method of any of claims 1 to 26, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered via a pressurized metered inhaler. 31. A compound of formula (I) or its pharmaceutically acceptable salt as defined in claim 1, used for the treatment or prevention of a disease or ailment in which JAK1 inhibition is beneficial, wherein the treatment comprises administering the compound of formula (I) or its pharmaceutically acceptable salt to an individual at a daily dose of 0.8 mg to 6.2 mg of free base. 32. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 31, wherein the inhibition of JAK1 is a beneficial disease or condition selected from type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata. 33. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 32, wherein the inhibition of JAK1 is a beneficial disease or condition of asthma. 34. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 32, wherein the inhibition of JAK1 is a beneficial disease or condition of COPD. 35. The compound of formula (I) or its pharmaceutically acceptable salt thereof, as stated in any of claims 31 to 34, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of at least 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, or 4.6 mg daily. Administer daily doses of free base at doses of 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, or 5.5 mg. 36. The compound of formula (I) or its pharmaceutically acceptable salt thereof, as stated in any of claims 31 to 34, wherein the compound of formula (I) or its pharmaceutically acceptable salt thereof is present in doses of up to 6.2 mg, 6.1 mg, 6.0 mg, 5.9 mg, 5.8 mg, 5.7 mg, 5.6 mg, 5.5 mg, 5.4 mg, 5.3 mg, 5.2 mg, 5.1 mg, 5.0 mg, 4.9 mg, 4.8 mg, 4.7 mg, 4.6 mg, 4.5 mg, 4.4 mg, 4.3 mg, 4.2 mg, 4.1 mg, 4.0 mg, 3.9 mg, 3.8 mg, 3.7 mg, 3.6 mg, 3.5 mg, 3.4 mg, 3.3 mg, 3.2 mg, 3.1 mg, 3.0 mg, 2.9 mg, 2.8 mg, 2.7 mg, 2.6 mg, 2.5 mg, or 2.5 mg per day. 37. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as stated in any of claims 31 to 36, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 2.8 mg of free base. 38. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 36, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 1.8 mg of free base. 39. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 36, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 0.8 mg of free base. 40. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 36, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 6.0 mg of free base. 41. The compound of formula (I) or its pharmaceutically acceptable salt thereof, as stated in any of claims 31 to 36, wherein the compound of formula (I) or its pharmaceutically acceptable salt thereof is administered in a delivery dose of 0.4 to 3.1 mg of free base twice daily. 42. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as stated in claim 41, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of at least 0.4 mg twice daily, 0.45 mg twice daily, 0.5 mg twice daily, 0.6 mg twice daily, 0.65 mg twice daily, 0.7 mg twice daily, 0.75 mg twice daily, 0.8 mg twice daily, 0.85 mg twice daily, 0.9 mg twice daily, 0.95 mg twice daily, 1.0 mg twice daily, 1.05 mg twice daily, 1.1 mg twice daily, 1.15 mg twice daily, 1.2 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, etc. Dosage of free bases: 1.6 mg twice daily, 1.65 mg twice daily, 1.7 mg twice daily, 1.75 mg twice daily, 1.8 mg twice daily, 1.85 mg twice daily, 1.9 mg twice daily, 2.0 mg twice daily, 2.05 mg twice daily, 2.1 mg twice daily, 2.15 mg twice daily, 2.2 mg twice daily, 2.25 mg twice daily, 2.3 mg twice daily, 2.35 mg twice daily, 2.4 mg twice daily, 2.45 mg twice daily, 2.5 mg twice daily, 2.55 mg twice daily, 2.6 mg twice daily, 2.7 mg twice daily, or 2.75 mg twice daily. 43. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as stated in claim 41, wherein the compound of formula (I) or its pharmaceutically acceptable salt is supplied in doses of up to 3.1 mg twice daily, 3.05 mg twice daily, 3.0 mg twice daily, 2.95 mg twice daily, 2.9 mg twice daily, 2.85 mg twice daily, 2.8 mg twice daily, 2.75 mg twice daily, 2.7 mg twice daily, 2.65 mg twice daily, 2.6 mg twice daily, 2.55 mg twice daily, 2.5 mg twice daily, 2.45 mg twice daily, 2.4 mg twice daily, 2.35 mg twice daily, 2.3 mg twice daily, 2.25 mg twice daily, 2.2 mg twice daily, 2.15 mg twice daily, 2.1 mg twice daily, 2.05 mg twice daily, 2.0 ... 1.95 mg twice daily, 1.9 mg twice daily, 1.85 mg twice daily, 1.8 mg twice daily, 1.75 mg twice daily, 1.7 mg twice daily, 1.65 mg twice daily, 1.6 mg twice daily, 1.55 mg twice daily, 1.5 mg twice daily, 1.45 mg twice daily, 1.4 mg twice daily, 1.35 mg twice daily, 1.3 mg twice daily, 1.25 mg twice daily, 1.2 mg twice daily, 1.15 mg twice daily, 1.1 mg twice daily, 1.05 mg twice daily, 1.0 mg twice daily, 0.95 mg twice daily, 0.9 mg twice daily, 0.85 mg twice daily, 0.8 mg twice daily, 0.75 mg twice daily, 0.7 mg twice daily, 0.65 mg twice daily, 0.6 mg twice daily. 44. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as claimed in claim 42 or claim 43, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 1.4 mg of free base twice daily. 45. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as claimed in claim 42 or claim 43, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 0.9 mg of free base twice daily. 46. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as stated in claim 42 or 43, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 0.4 mg free base twice daily. 47. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as stated in claim 42 or 43, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 3.0 mg free base twice daily. 48. The compound of formula (I) or its pharmaceutically acceptable salt supplied for use as stated in any of claims 31 to 47, wherein the compound of formula (I) is administered as a pharmaceutically acceptable salt. 49. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 48, wherein the compound of formula (I) is administered as a sennarate salt. 50. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 34 or 49, wherein the compound of formula (I) is administered as a sennarate salt at a daily dose of 1.05 mg to 8.14 mg sennarate. 51. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 50, wherein the sennarate salt of the compound of formula (I) is administered at a daily dose of 1.84 mg sennarate. 52. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 50, wherein the sennarate of formula (I) is administered at a dose of 1.18 mg sennarate twice daily. 53. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 50, wherein the sennarate of formula (I) is administered at a dose of 0.53 mg sennarate twice daily. 54. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 50, wherein the sennarate of formula (I) is administered at a dose of 3.94 mg sennarate twice daily. 55. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 34 to 40, wherein the dose interval is 10 to 14 hours. 56. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 55, wherein the dose interval is 11 hours and 30 minutes to 12 hours and 30 minutes. 57. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 56, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered orally. 58. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 56, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in the form of an inhaled aerosol. 59. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 56, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered via a dry powder inhaler. 60. The compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 31 to 56, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered via a pressurized metered inhaler. 61. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in Statement 1 for the manufacture of a medicament for the treatment or prevention of a disease or ailment in which JAK1 inhibition is beneficial, wherein the treatment comprises administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof at a daily dose of 0.8 mg to 6.2 mg of free base. 62. The use of a compound of formula (I) of claim 61 or a medically acceptable salt thereof, wherein the inhibition of JAK1 is a beneficial disease or condition selected from type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis arthritis, juvenile idiopathic arthritis, axial spondylitis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata. 63. The use of a compound of formula (I) of claim 62 or a medically acceptable salt thereof, wherein the inhibition of JAK1 is a beneficial disease or condition of asthma. 64. The use of a compound of formula (I) of claim 62 or a medically acceptable salt thereof, wherein the inhibition of JAK1 is a beneficial disease or condition of COPD. 65. Use of any compound of formula (I) or its pharmaceutically acceptable salt as stated in claims 61 to 64, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of at least 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, or 4.6 mg daily. Administer daily doses of free base at doses of 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, or 5.5 mg. 66. Use of any compound of formula (I) or its pharmaceutically acceptable salt as stated in claims 61 to 64, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in doses of up to 6.2 mg, 6.1 mg, 6.0 mg, 5.9 mg, 5.8 mg, 5.7 mg, 5.6 mg, 5.5 mg, 5.4 mg, 5.3 mg, 5.2 mg, 5.1 mg, 5.0 mg, 4.9 mg, 4.8 mg, 4.7 mg, 4.6 mg, 4.5 mg, 4.4 mg, 4.3 mg, 4.2 mg, 4.1 mg, 4.0 mg, 3.9 mg, 3.8 mg, 3.7 mg, 3.6 mg, 3.5 mg, 3.4 mg, 3.3 mg, 3.2 mg, 3.1 mg, 3.0 mg, 2.9 mg, 2.8 mg, 2.7 mg, 2.6 mg, 2.5 mg, or 2.5 mg per day. 67. Administer a daily dose of free base of 2.8 mg, 2.4 mg, 2.3 mg, 2.2 mg, 2.1 mg, 2.0 mg, 1.9 mg, 1.8 mg, 1.7 mg, 1.6 mg, 1.5 mg, 1.4 mg, 1.3 mg, 1.2 mg, 1.1 mg, or 1.0 mg. 68. Use of any compound of formula (I) or its pharmaceutically acceptable salt as stated in claims 61 to 66, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 2.8 mg of free base. 68. Use of any compound of formula (I) or its pharmaceutically acceptable salt as claimed in claims 61 to 66, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 1.8 mg of free base. 69. Use of any compound of formula (I) or its pharmaceutically acceptable salt as claimed in claims 61 to 66, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 0.8 mg of free base. 70. Use of any compound of formula (I) or its pharmaceutically acceptable salt as claimed in claims 61 to 66, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of 6.0 mg of free base. 71. Use of any of the compounds of formula (I) or their pharmaceutically acceptable salts as stated in claims 61 to 70, wherein the compounds of formula (I) or their pharmaceutically acceptable salts are administered in a delivery dose of 0.4 to 3.1 mg of free base twice daily. 72. The use of any compound of formula (I) or its pharmaceutically acceptable salt as stated in claims 61 to 71, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of at least 0.4 mg twice daily, 0.45 mg twice daily, 0.5 mg twice daily, 0.6 mg twice daily, 0.65 mg twice daily, 0.7 mg twice daily, 0.75 mg twice daily, 0.8 mg twice daily, 0.85 mg twice daily, 0.9 mg twice daily, 0.95 mg twice daily, 1.0 mg twice daily, 1.05 mg twice daily, 1.1 mg twice daily, 1.15 mg twice daily, 1.2 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, 1.55 mg twice daily, 1.25 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, 1.2 ... Dosage of free bases: 1.6 mg twice daily, 1.65 mg twice daily, 1.7 mg twice daily, 1.75 mg twice daily, 1.8 mg twice daily, 1.85 mg twice daily, 1.9 mg twice daily, 2.0 mg twice daily, 2.05 mg twice daily, 2.1 mg twice daily, 2.15 mg twice daily, 2.2 mg twice daily, 2.25 mg twice daily, 2.3 mg twice daily, 2.35 mg twice daily, 2.4 mg twice daily, 2.45 mg twice daily, 2.5 mg twice daily, 2.55 mg twice daily, 2.6 mg twice daily, 2.7 mg twice daily, or 2.75 mg twice daily. 73. As stated in claims 61 to 71, the use of any compound of formula (I) or its pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or its pharmaceutically acceptable salt (as the case may be in the form of a pharmaceutically acceptable salt) is administered in doses of up to 3.1 mg twice daily, 3.05 mg twice daily, 3.0 mg twice daily, 2.95 mg twice daily, 2.9 mg twice daily, 2.85 mg twice daily, 2.8 mg twice daily, 2.75 mg twice daily, 2.7 mg twice daily, 2.65 mg twice daily, 2.6 mg twice daily, 2.55 mg twice daily, 2.5 mg twice daily, 2.45 mg twice daily, 2.4 mg twice daily, 2.35 mg twice daily, 2.3 mg twice daily, 2.25 mg twice daily, 2.2 mg twice daily, 2.15 mg twice daily, etc. 2.1 mg twice daily, 2.05 mg twice daily, 2.0 mg twice daily, 1.95 mg twice daily, 1.9 mg twice daily, 1.85 mg twice daily, 1.8 mg twice daily, 1.75 mg twice daily, 1.7 mg twice daily, 1.65 mg twice daily, 1.6 mg twice daily, 1.55 mg twice daily, 1.5 mg twice daily, 1.45 mg twice daily, 1.4 mg twice daily, 1.35 mg twice daily, 1.3 mg twice daily, 1.25 mg twice daily, 1.2 mg twice daily, 1.15 mg twice daily, 1.1 mg twice daily, 1.05 mg twice daily, 1.0 mg twice daily, 0.95 mg twice daily, 0.9 mg twice daily, 0.85 mg twice daily, 0.8 mg twice daily, 0.75 mg twice daily, 0.7 mg twice daily. 74. The use of any compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 73, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 1.4 mg of free base twice daily. 75. The use of any compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 73, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 0.9 mg of free base twice daily. 76. Use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 71, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 0.4 mg free base twice daily. 77. Use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 71, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of 3.0 mg free base twice daily. 78. Use of the compound of formula (I) as claimed in any of claims 61 to 77, wherein the compound of formula (I) is administered as a pharmaceutically acceptable salt. 79. Use of the compound of formula (I) as claimed in claim 78, wherein the compound of formula (I) is administered as a sine arabinate salt. 80. The use of the compound of formula (I) as claimed in any of claims 61 to 64 or 79, wherein the compound of formula (I) is administered as a sinephrine at a daily dose of 1.05 mg to 8.14 mg sinephrine. 81. The use of the compound of formula (I) as claimed in claim 80, wherein the sinephrine of the compound of formula (I) is administered at a daily dose of 1.84 mg sinephrine. 82. The use of the compound of formula (I) as claimed in claim 80, wherein the sinephrine of the compound of formula (I) is administered at a daily dose of 1.18 mg sinephrine. 83. The use of compound (I) of formula (I) as claimed in claim 80, wherein the sennarate of formula (I) is administered in a dose of 0.53 mg sennarate twice daily. 84. The use of compound (I) of formula (I) as claimed in claim 80, wherein the sennarate of formula (I) is administered in a dose of 3.94 mg sennarate twice daily. 85. The use of compound (I) of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any of claims 71 to 79 or 81 to 84, wherein the dose interval is between 10 and 14 hours. 86. The use of compound (I) of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 85, wherein the dose interval is between 11 hours and 30 minutes and 12 hours and 30 minutes. 87. Use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 86, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered orally. 88. Use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 87, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in the form of an inhaled aerosol. 89. Use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 61 to 88, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered via a dry powder inhaler. 90. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any of claims 61 to 88, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered via a pressurized metered-dose inhaler. 91. A kit for treating or preventing diseases or disorders in which JAK1 inhibition is beneficial, the kit comprising an inhaler for administering a compound of formula (I) at a daily dose of 0.8 mg to 6.2 mg of free base, wherein the compound of formula (I) may be in the form of a pharmaceutically acceptable salt. 92. The kit of claim 91, wherein the inhaler is a dry powder inhaler. 93. The kit of claim 91, wherein the inhaler is a pressurized metered-dose inhaler. 94. An inhaler configured to deliver a compound of formula (I) at a delivery dose of 0.4 mg to 3.1 mg of free base, wherein the compound of formula (I) may be in the form of a pharmaceutically acceptable salt. 95. The inhaler of claim 94, wherein the inhaler is a dry powder inhaler. 96. The inhaler of claim 94, wherein the inhaler is a pressurized metered-dose inhaler.

Figure 1 shows the pharmacokinetic (PK) data for Phase 1-Part 1a (single escalating dose) of the clinical trial administered on day 1 for seven different doses, i.e., geometric mean plasma concentration (nmol/L) of compound 1 versus time. Figure 2 shows the PK data for Phase 1-Part 1b of the clinical trial administered on day 1 for two different doses (0.3 mg IV and 1 mg oral), i.e., geometric mean plasma concentration (nmol/L) of compound 1 versus time. Figures 3 and 4 show the pharmacokinetic (PK) data for Phase 1 Part 2 (multiple escalation doses, twice daily) of the clinical trial administered as a dry powder inhaler (DPI) on Day 1 (Figure 3) and Day 7 (Figure 4), i.e., geometric mean plasma concentration (nmol/L) of compound 1 versus time. Figure 5 shows the PK data for Phase 1 Part 3 of the clinical trial following a single dose of 1.4 mg and 3 mg of compound 1 as a dry powder inhaler in patients with mild asthma on Day 1, i.e., geometric mean plasma concentration (nmol/L) of compound 1 versus time. Figure 6. PK data of Phase 1 Part 3 of the clinical trial, i.e., geometric mean plasma concentration (nmol/L) of compound 1 as a dry powder inhaler, after multiple BID doses of 1.4 mg and 3 mg of compound 1 as a dry powder inhaler in patients with mild asthma on day 10. Figure 7. Relative change of FeNO from baseline within 2 hours after morning dose of 1.4 mg and 3 mg BID of compound 1 (MMRM analysis plot at time points, Part 3, safety analysis set). Figure 8. Graph of Phase 1 (Part 1a (SAD) and Part 1b (oral and IV)) clinical trials. Figure 9. Graph of Phase 1 Part 2 clinical trial. Figure 10. Graph of Phase 1 Part 3 clinical trial.

Claims (27)

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) It is used to manufacture a medicine for treating or preventing diseases or disorders in which JAK1 inhibition is beneficial, wherein the treatment comprises administering to an individual a compound of formula (I) or a pharmaceutically acceptable salt thereof at a daily dose of 0.8 mg to 6.2 mg of free base. The use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 1, wherein inhibition of JAK1 is beneficial for the disease or condition being asthma or COPD. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of at least 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, or 4.6 mg daily. Administer daily doses of free base at doses of 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, or 5.5 mg. The use of any of the compounds of formula (I) or their pharmaceutically acceptable salts as claimed in items 1 to 3, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in doses of up to 6.2 mg, 6.1 mg, 6.0 mg, 5.9 mg, 5.8 mg, 5.7 mg, 5.6 mg, 5.5 mg, 5.4 mg, 5.3 mg, 5.2 mg, 5.1 mg, 5.0 mg, 4.9 mg, 4.8 mg, 4.7 mg, 4.6 mg, 4.5 mg, 4.4 mg, 4.3 mg, 4.2 mg, 4.1 mg, 4.0 mg, 3.9 mg, 3.8 mg, 3.7 mg, 3.6 mg, 3.5 mg, 3.4 mg, 3.3 mg, 3.2 mg, 3.1 mg, 3.0 mg, 2.9 mg, 2.8 mg, 2.7 mg, 2.6 mg, 2.5 mg, or 2.5 mg per day. Administer daily doses of free base at doses of 2.4 mg, 2.3 mg, 2.2 mg, 2.1 mg, 2.0 mg, 1.9 mg, 1.8 mg, 1.7 mg, 1.6 mg, 1.5 mg, 1.4 mg, 1.3 mg, 1.2 mg, 1.1 mg, or 1.0 mg. For the use of any of the claims 1 to 4, the compound of formula (I) or its pharmaceutically acceptable salt is administered at a daily dose of any of the following: (a) 2.8 mg free base; (b) 1.8 mg free base; (c) 0.8 mg free base; and (d) 6.0 mg free base. The use of any of the formula (I) compounds or their pharmaceutically acceptable salts as claimed in claims 1 to 4, wherein the formula (I) compound or its pharmaceutically acceptable salt is administered in a delivery dose of 0.4 to 3.1 mg of free base twice daily. For example, the use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 6, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered at a dose of at least 0.4 mg twice daily, 0.45 mg twice daily, 0.5 mg twice daily, 0.6 mg twice daily, 0.65 mg twice daily, 0.7 mg twice daily, 0.75 mg twice daily, 0.8 mg twice daily, 0.85 mg twice daily, 0.9 mg twice daily, 0.95 mg twice daily, 1.0 mg twice daily, 1.05 mg twice daily, 1.1 mg twice daily, 1.15 mg twice daily, 1.2 mg twice daily, 1.25 mg twice daily, 1.3 mg twice daily, 1.35 mg twice daily, 1.4 mg twice daily, 1.45 mg twice daily, 1.5 mg twice daily, 1.55 mg twice daily, etc. Dosage of free bases: 1.6 mg twice daily, 1.65 mg twice daily, 1.7 mg twice daily, 1.75 mg twice daily, 1.8 mg twice daily, 1.85 mg twice daily, 1.9 mg twice daily, 2.0 mg twice daily, 2.05 mg twice daily, 2.1 mg twice daily, 2.15 mg twice daily, 2.2 mg twice daily, 2.25 mg twice daily, 2.3 mg twice daily, 2.35 mg twice daily, 2.4 mg twice daily, 2.45 mg twice daily, 2.5 mg twice daily, 2.55 mg twice daily, 2.6 mg twice daily, 2.7 mg twice daily, or 2.75 mg twice daily. The use of the compound of formula (I) or its pharmaceutically acceptable salt, as claimed in claim 6 or 7, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in doses of up to 3.1 mg twice daily, 3.05 mg twice daily, 3.0 mg twice daily, 2.95 mg twice daily, 2.9 mg twice daily, 2.85 mg twice daily, 2.8 mg twice daily, 2.75 mg twice daily, 2.7 mg twice daily, 2.65 mg twice daily, 2.6 mg twice daily, 2.55 mg twice daily, 2.5 mg twice daily, 2.45 mg twice daily, 2.4 mg twice daily, 2.35 mg twice daily, 2.3 mg twice daily, 2.25 mg twice daily, 2.2 mg twice daily, 2.15 mg twice daily, 2.1 mg twice daily, 2.05 mg twice daily, 2.0 mg twice daily, etc. 1.95 mg twice daily, 1.9 mg twice daily, 1.85 mg twice daily, 1.8 mg twice daily, 1.75 mg twice daily, 1.7 mg twice daily, 1.65 mg twice daily, 1.6 mg twice daily, 1.55 mg twice daily, 1.5 mg twice daily, 1.45 mg twice daily, 1.4 mg twice daily, 1.35 mg twice daily, 1.3 mg twice daily, 1.25 mg twice daily, 1.2 mg twice daily, 1.15 mg twice daily, 1.1 mg twice daily, 1.05 mg twice daily, 1.0 mg twice daily, 0.95 mg twice daily, 0.9 mg twice daily, 0.85 mg twice daily, 0.8 mg twice daily, 0.75 mg twice daily, 0.7 mg twice daily, 0.65 mg twice daily, 0.6 mg twice daily. The delivery dose of free base is 0.55 mg twice daily, 0.55 mg twice daily, or 0.5 mg twice daily. For the use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 7 or 8, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in any of the following dosages: (a) 1.4 mg free base twice daily; (b) 0.9 mg free base twice daily; (c) 0.4 mg free base twice daily; and (d) 3.0 mg free base twice daily. The use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 9, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in a delivery dose of 1.4 mg of free base twice daily. The use of any of the claims 1 to 10 for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is administered as a pharmaceutically acceptable salt. The use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 11, wherein the compound of formula (I) is administered as a xinafoate salt. The use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in any of claims 1, 2 and 11, wherein the compound of formula (I) is administered as a sinetate at a daily delivery dose of 1.05 mg to 8.14 mg. For the use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 13, wherein the cinnamate salt of the compound of formula (I) is administered in any of the following doses: (a) 1.84 mg cinnamate twice daily; (b) 1.18 mg cinnamate twice daily; (c) 0.53 mg cinnamate twice daily; and (d) 3.94 mg cinnamate twice daily. For example, the use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 14, wherein the sinetate of the compound of formula (I) is administered in a delivery dose of 1.84 mg of the sinetate twice daily. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as provided in any of claims 6 to 10 or claims 14 to 15, wherein the doses are administered at intervals of 10 to 14 hours. The use of the compound of formula (I) or its pharmaceutically acceptable salt as claimed in claim 16, wherein the doses are administered at intervals of 11 hours and 30 minutes to 12 hours and 30 minutes. The use of any of the claims 1 to 17 for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered orally. The use of any of the formula (I) compounds or their pharmaceutically acceptable salts as claimed in any of claims 1 to 17, wherein the formula (I) compound or its pharmaceutically acceptable salt is administered in the form of an inhaled aerosol. Use of any of the formula (I) compounds or their pharmaceutically acceptable salts as claimed in any of claims 1 to 17, wherein the formula (I) compound or its pharmaceutically acceptable salt is administered via a dry powder inhaler. The use of any of the formula (I) compounds or their pharmaceutically acceptable salts as claimed in any of claims 1 to 17, wherein the formula (I) compound or its pharmaceutically acceptable salt is administered via a pressurized metered inhaler. A kit for the treatment or prevention of diseases or disorders in which JAK1 inhibition is beneficial, the kit comprising an inhaler for delivering a type (I) compound in a daily dose of 0.8 mg to 6.2 mg of free base: (I), wherein the compound of formula (I) may be in the form of a pharmaceutically acceptable salt. As in the kit of request item 22, wherein the inhaler is a dry powder inhaler. The kit in Request 22, wherein the inhaler is a pressurized metered-dose inhaler. An inhaler configured to deliver compound (I) in doses of 0.4 mg to 3.1 mg of free base: (I), wherein the compound of formula (I) may be in the form of a pharmaceutically acceptable salt. The inhaler in claim 25, wherein the inhaler is a dry powder inhaler. The inhaler in claim 25, wherein the inhaler is a pressurized metered-dose inhaler.